DOCSLIB.ORG

Primate-Specific Histone Variants

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Genome Primate-specific histone variants Journal: Genome Manuscript ID gen-2020-0094.R1 Manuscript Type: Mini Review Date Submitted by the 16-Sep-2020 Author: Complete List of Authors: Ding, Dongbo; Hong Kong University of Science and Technology School of Science, Division of Life Science NGUYEN, Thi Thuy; Hong Kong University of Science and Technology School of Science, Division of Life Science Pang, Matthew Yu Hin; Hong Kong University of Science and Technology School of Science, Division of Life Science Ishibashi, DraftToyotaka; Hong Kong University of Science and Technology School of Science, Division of Life Science Keyword: histone variant, H2BFWT, H3.5, H3.X, H3.Y Is the invited manuscript for consideration in a Special Genome Biology Issue? : © The Author(s) or their Institution(s) Page 1 of 28 Genome 1 Primate-specific histone variants 2 Dongbo Ding1, Thi Thuy Nguyen1, Matthew Y.H. Pang1 and Toyotaka 3 Ishibashi1 4 1. Division of Life Science, The Hong Kong University of Science and Technology, 5 Clear Water Bay, NT, HKSAR, China 6 7 8 9 10 11 12 Draft 13 14 15 16 17 18 19 Correspondence should be addressed to : 20 Toyotaka Ishibashi 21 The Hong Kong University of Science and Technology 22 Clear Water Bay, NT, HKSAR, China 23 E-mail: [email protected] 24 Phone: +852-3469-2238 25 Fax: +852-2358-1552 26 © The Author(s) or their Institution(s) Genome Page 2 of 28 27 Abstract 28 29 Canonical histones (H2A, H2B, H3, and H4) are present in all eukaryotes where they 30 package genomic DNA and participate in numerous cellular processes, such as 31 transcription regulation and DNA repair. In addition to the canonical histones, there 32 are many histone variants, which have different amino acid sequences, possess tissue- 33 specific expression profiles, and function distinctly from the canonical counterparts. A 34 number of histone variants, including both core histones (H2A/H2B/H3/H4) and 35 linker histones (H1/H5), have been identified to date. Htz1 (H2A.Z) and CENP-A 36 (CenH3) are present from yeasts to mammals, and H3.3 is present from Tetrahymena 37 to humans. In addition to the prevalent variants, others like H3.4 (H3t), H2A.Bbd, and 38 TH2B, as well as several H1 variants,Draft are found to be specific to mammals. Among 39 them, H2BFWT, H3.5, H3.X, H3.Y, and H4G are unique to primates (or Hominidae). 40 In this review, we focus on localization and function of primate- or hominidae- 41 specific histone variants. 42 43 44 45 Key Words 46 47 Histone variants, H2BFWT, H3.5, H3.X, H3.Y, H4G 48 © The Author(s) or their Institution(s) Page 3 of 28 Genome 49 50 1. Telomere-localized and spermatogenesis-specific histone variants, H2BFWT 51 52 Histone H2B, one of the four canonical histones involved in chromatin formation, 53 has several canonical isoforms (Molden et al. 2015) and two variants: TH2B and 54 H2BFWT, both of which have been identified as testis-specific histones. TH2B is 55 present in later stages of spermatogenesis and is expressed in most mammalian 56 species (Montellier et al. 2013), whereas H2BFWT is expressed only in primates. 57 H2BFWT is also known as H2BW1, is located at the locus Xq22.2 in humans (Table 58 1). The H2BFWT protein shares 43% amino acid sequence identity with the 59 canonical H2B, and 46% identity with TH2B (Figure 1). H2BFWT was reported to 60 be 153 amino acid residues long inDraft vivo with an extended N-terminal tail compared 61 to canonical H2B (Boulard et al. 2006). 62 63 GFP-H2BFWT was found to mainly localize in the telomeric region in Chinese 64 hamster immortal lung fibroblasts (the V79 cell line) (Churikov et al. 2004). 65 However, there is limited knowledge about its function in the telomeric region. 66 H2BFWT can also be loaded into nucleosomes using in vitro salt gradient dialysis 67 methods, and these reconstituted H2BFWT nucleosomes can be remodeled and 68 mobilized by the SWI/SNF chromatin remodeling complex more efficiently than that 69 the canonical nucleosomes (Boulard et al. 2006). In contrast to canonical H2B, 70 H2BFWT was reported to be unable to recruit chromosome condensation factors and 71 participate in the assembly of mitotic chromosomes (Boulard et al. 2006). 72 © The Author(s) or their Institution(s) Genome Page 4 of 28 73 Several studies have suggested a relationship between single nucleotide 74 polymorphisms (SNPs) in H2BFWT and defects in male fertility (Lee et al. 2009; 75 Rafatmanesh et al. 2018; Ying et al. 2012). In particular, three groups have linked the 76 -9C > T mutation (rs7885967) within the 5’ untranslated region of H2BFWT to non- 77 azoospermia (p = 0.018), a reduced sperm count (p = 0.0127) and a weakened sperm 78 vitality (p = 0.0076) (Lee et al. 2009; Rafatmanesh et al. 2018; Ying et al. 2012). A 79 related investigation by Ying et al. revealed that the 368A > G mutation (rs553509) 80 increased the risk of male sterility (Ying et al. 2012)(Figure 2). 81 82 A more contemporary analysis assessing copy number variations in chromosome X 83 revealed that 5 out of 42 female participants with premature ovarian failure suffer 84 from either gains or losses of genomicDraft regions containing H2BFWT and H2BFM (an 85 uncharacterized histone variant located near H2BFWT) (Quilter et al. 2010). 86 Considering the highly testis-specific expression pattern of H2BFWT and the 87 detectable expression of H2BFM in the ovary (Papatheodorou et al. 2020), it is not 88 unreasonable to speculate that the premature ovarian failure phenotype stems from 89 the deletion of H2BFM but not H2BFWT. However, the possibilities of a correlation 90 between mutations in both H2BFWT and H2BFM, and premature ovarian failures 91 cannot be ignored, especially when detailed expression profiles of H2BFWT and 92 H2BFM in female reproductive organs are currently unavailable. Compounded by 93 the fact that the biological role of H2BFM has yet to be explored, further research is 94 necessary to evaluate these hypotheses. Although H2BFWT SNPs increase the 95 probability of infertility, it is possible that H2BFWT is not the only causative factor. 96 It would also be interesting to study its combination with another histone variant’s 97 mutation contributing to infertility. Further characterization of H2BFWT would be © The Author(s) or their Institution(s) Page 5 of 28 Genome 98 helpful to understand how it might contribute to spermatogenesis and other cellular 99 processes. 100 101 Regarding the H2B family, other than H2BFWT, little attention has been given to 102 multi-copied canonical H2B isoforms, which differ from each other by a few amino 103 acids. Most of them are currently grouped together as canonical H2Bs due to their 104 high similarity (Molden et al. 2015). Most changes in these isoforms are small and 105 have minor effects on the H2B protein structure, although some isoforms such as 106 H2B1L, H2B1M, and H2B1A could possess an alternative N-terminal tail 107 conformation (Molden et al. 2015). It remains unknown if these structural 108 modifications can cause distinct functions or localizations compared to canonical 109 H2B, but it would be interestingDraft to study how the N-terminal tail of H2B can 110 contribute to nucleosome stability, change the chromatin structure, interact with other 111 proteins, cause distinct genomic localization, and potentially alter post-translational 112 modification patterns if critical amino acid residues are changed. 113 114 2. Testis-specific histone variant H3.5 regulates spermatogenesis while H3.X and 115 H3.Y express in the brain 116 117 The histone H3 family has several histone variants, but although their sequences are 118 similar, they have distinct functions (Buschbeck and Hake 2017). For example, H3.3 119 is widely expressed and is localized in the promoter region of actively expressed 120 genes, while another histone variant, H3T (H3.4), is only present in the testis and 121 plays a critical role in the dynamics of chromatin transitions during spermatogenesis 122 (Ausio et al. 2016; Yuen et al. 2014). In primates, three additional H3 variants have © The Author(s) or their Institution(s) Genome Page 6 of 28 123 been identified; H3.5 (also known as H3.3C) (Schenk et al. 2011; Ederveen et al. 124 2011), H3.X, and H3.Y (Wiedemann et al. 2010). 125 126 The H3.5 gene is localized in the 12p11.21 region of human chromosome 12 (Schenk 127 et al. 2011). The amino acid sequence of H3.5 is most similar to that of histone 128 variant H3.3, which is involved in the maintenance of transcriptionally active 129 chromatin (Mito et al. 2005). The H3.X and H3.Y genes were identified at the same 130 time and are located at the 5p15.1 chromosome region in humans (Wiedemann et al. 131 2010). Both H3.X and H3.Y are expressed in the same tissues and are considered to 132 have similar functions, including regulating the cell cycle and facilitating DUX4 133 target genes expression (Resnick etDraft al. 2019; Wiedemann et al. 2010). 134 135 Histone variant H3.5 varies by five amino acid residues from H3.3 (Figure 1). As a 136 result, the H3.5 nucleosome has lower nucleosome stability than the H3.3 137 nucleosome, but it is more stable than the H3.4 (H3T) nucleosome (Urahama et al. 138 2016). This decrease in nucleosome stability can mainly be attributed to the H3.5L103 139 residue which weakens the interaction between H3.5 and H4 (Urahama et al. 2016). 140 The H3.5/H4 tetrasome is also less stable than the H3.3/H4 tetrasome (Urahama et al.
Recommended publications
  • Histone Variants: Deviants?

    Histone Variants: Deviants?

    Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Histone variants: deviants? Rohinton T. Kamakaka2,3 and Sue Biggins1 1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 2UCT/National Institutes of Health, Bethesda, Maryland 20892, USA Histones are a major component of chromatin, the pro- sealing the two turns of DNA. The nucleosome filament tein–DNA complex fundamental to genome packaging, is then folded into a 30-nm fiber mediated in part by function, and regulation. A fraction of histones are non- nucleosome–nucleosome interactions, and this fiber is allelic variants that have specific expression, localiza- probably the template for most nuclear processes. Addi- tion, and species-distribution patterns. Here we discuss tional levels of compaction enable these fibers to be recent progress in understanding how histone variants packaged into the small volume of the nucleus. lead to changes in chromatin structure and dynamics to The packaging of DNA into nucleosomes and chroma- carry out specific functions. In addition, we review his- tin positively or negatively affects all nuclear processes tone variant assembly into chromatin, the structure of in the cell. While nucleosomes have long been viewed as the variant chromatin, and post-translational modifica- stable entities, there is a large body of evidence indicat- tions that occur on the variants. ing that they are highly dynamic (for review, see Ka- makaka 2003), capable of being altered in their compo- Supplemental material is available at http://www.genesdev.org. sition, structure, and location along the DNA. Enzyme Approximately two meters of human diploid DNA are complexes that either post-translationally modify the packaged into the cell’s nucleus with a volume of ∼1000 histones or alter the position and structure of the nucleo- µm3.
  • Abnormal Developmental Control of Replication-Timing Domains in Pediatric Acute Lymphoblastic Leukemia

    Abnormal Developmental Control of Replication-Timing Domains in Pediatric Acute Lymphoblastic Leukemia

    Downloaded from genome.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Research Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia Tyrone Ryba,1,6 Dana Battaglia,1,6 Bill H. Chang,2 James W. Shirley,1 Quinton Buckley,1 Benjamin D. Pope,1 Meenakshi Devidas,3 Brian J. Druker,4,5 and David M. Gilbert1,7 1Department of Biological Science, Florida State University, Tallahassee, Florida 32306, USA; 2Division of Hematology and Oncology, Department of Pediatrics, and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, USA; 3COG and Department of Biostatistics, College of Medicine, University of Florida, Gainesville, Florida 32601, USA; 4Division of Hematology and Medical Oncology, and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, USA; 5Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication-timing profiles for pediatric leukemias from 17 patients and three cell lines, as well as normal B and T cells. Nonleukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replication- timing profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than nonleukemic controls. Some differences were patient specific, while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, dif- ferences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replication- timing domains that distinguish normal cell types.
  • The Role of Histone H2av Variant Replacement and Histone H4 Acetylation in the Establishment of Drosophila Heterochromatin

    The Role of Histone H2av Variant Replacement and Histone H4 Acetylation in the Establishment of Drosophila Heterochromatin

    The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin Jyothishmathi Swaminathan, Ellen M. Baxter, and Victor G. Corces1 Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA Activation and repression of transcription in eukaryotes involve changes in the chromatin fiber that can be accomplished by covalent modification of the histone tails or the replacement of the canonical histones with other variants. Here we show that the histone H2A variant of Drosophila melanogaster, H2Av, localizes to the centromeric heterochromatin, and it is recruited to an ectopic heterochromatin site formed by a transgene array. His2Av behaves genetically as a PcG gene and mutations in His2Av suppress position effect variegation (PEV), suggesting that this histone variant is required for euchromatic silencing and heterochromatin formation. His2Av mutants show reduced acetylation of histone H4 at Lys 12, decreased methylation of histone H3 at Lys 9, and a reduction in HP1 recruitment to the centromeric region. H2Av accumulation or histone H4 Lys 12 acetylation is not affected by mutations in Su(var)3-9 or Su(var)2-5. The results suggest an ordered cascade of events leading to the establishment of heterochromatin and requiring the recruitment of the histone H2Av variant followed by H4 Lys 12 acetylation as necessary steps before H3 Lys 9 methylation and HP1 recruitment can take place. [Keywords: Chromatin; silencing; transcription; histone; nucleus] Received September 8, 2004; revised version accepted November 4, 2004. The basic unit of chromatin is the nucleosome, which is guchi et al. 2004). The role of histone variants, and spe- made up of 146 bp of DNA wrapped around a histone cially those of H3 and H2A, in various nuclear processes octamer composed of two molecules each of the histones has been long appreciated (Wolffe and Pruss 1996; Ah- H2A, H2B, H3, and H4.
  • A Yeast Phenomic Model for the Influence of Warburg Metabolism on Genetic Buffering of Doxorubicin Sean M

    A Yeast Phenomic Model for the Influence of Warburg Metabolism on Genetic Buffering of Doxorubicin Sean M

    Santos and Hartman Cancer & Metabolism (2019) 7:9 https://doi.org/10.1186/s40170-019-0201-3 RESEARCH Open Access A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin Sean M. Santos and John L. Hartman IV* Abstract Background: The influence of the Warburg phenomenon on chemotherapy response is unknown. Saccharomyces cerevisiae mimics the Warburg effect, repressing respiration in the presence of adequate glucose. Yeast phenomic experiments were conducted to assess potential influences of Warburg metabolism on gene-drug interaction underlying the cellular response to doxorubicin. Homologous genes from yeast phenomic and cancer pharmacogenomics data were analyzed to infer evolutionary conservation of gene-drug interaction and predict therapeutic relevance. Methods: Cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library were measured by quantitative high-throughput cell array phenotyping (Q-HTCP), treating with escalating doxorubicin concentrations under conditions of respiratory or glycolytic metabolism. Doxorubicin-gene interaction was quantified by departure of CPPs observed for the doxorubicin-treated mutant strain from that expected based on an interaction model. Recursive expectation-maximization clustering (REMc) and Gene Ontology (GO)-based analyses of interactions identified functional biological modules that differentially buffer or promote doxorubicin cytotoxicity with respect to Warburg metabolism. Yeast phenomic and cancer pharmacogenomics data were integrated to predict differential gene expression causally influencing doxorubicin anti-tumor efficacy. Results: Yeast compromised for genes functioning in chromatin organization, and several other cellular processes are more resistant to doxorubicin under glycolytic conditions. Thus, the Warburg transition appears to alleviate requirements for cellular functions that buffer doxorubicin cytotoxicity in a respiratory context.
  • Chew Et Al-2021-Nature Communi

    Chew Et Al-2021-Nature Communi

    Short H2A histone variants are expressed in cancer Guo-Liang Chew, Marie Bleakley, Robert Bradley, Harmit Malik, Steven Henikoff, Antoine Molaro, Jay Sarthy To cite this version: Guo-Liang Chew, Marie Bleakley, Robert Bradley, Harmit Malik, Steven Henikoff, et al.. Short H2A histone variants are expressed in cancer. Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.490. 10.1038/s41467-020-20707-x. hal-03118929 HAL Id: hal-03118929 https://hal.archives-ouvertes.fr/hal-03118929 Submitted on 22 Jan 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ARTICLE https://doi.org/10.1038/s41467-020-20707-x OPEN Short H2A histone variants are expressed in cancer Guo-Liang Chew 1, Marie Bleakley2, Robert K. Bradley 3,4,5, Harmit S. Malik4,6, Steven Henikoff 4,6, ✉ ✉ Antoine Molaro 4,7 & Jay Sarthy 4 Short H2A (sH2A) histone variants are primarily expressed in the testes of placental mammals. Their incorporation into chromatin is associated with nucleosome destabilization and modulation of alternate splicing. Here, we show that sH2As innately possess features similar to recurrent oncohistone mutations associated with nucleosome instability. Through 1234567890():,; analyses of existing cancer genomics datasets, we find aberrant sH2A upregulation in a broad array of cancers, which manifest splicing patterns consistent with global nucleosome destabilization.
  • Histone Variants: Guardians of Genome Integrity

    Histone Variants: Guardians of Genome Integrity

    cells Review Histone Variants: Guardians of Genome Integrity Juliette Ferrand y, Beatrice Rondinelli y and Sophie E. Polo * Epigenetics & Cell Fate Centre, UMR7216 CNRS, Université de Paris, 75013 Paris, France; [email protected] (J.F.); [email protected] (B.R.) * Correspondence: [email protected] These authors contributed equally. y Received: 1 October 2020; Accepted: 3 November 2020; Published: 5 November 2020 Abstract: Chromatin integrity is key for cell homeostasis and for preventing pathological development. Alterations in core chromatin components, histone proteins, recently came into the spotlight through the discovery of their driving role in cancer. Building on these findings, in this review, we discuss how histone variants and their associated chaperones safeguard genome stability and protect against tumorigenesis. Accumulating evidence supports the contribution of histone variants and their chaperones to the maintenance of chromosomal integrity and to various steps of the DNA damage response, including damaged chromatin dynamics, DNA damage repair, and damage-dependent transcription regulation. We present our current knowledge on these topics and review recent advances in deciphering how alterations in histone variant sequence, expression, and deposition into chromatin fuel oncogenic transformation by impacting cell proliferation and cell fate transitions. We also highlight open questions and upcoming challenges in this rapidly growing field. Keywords: cancer; cell fate; chromatin; chromosome integrity; DNA damage response; DNA repair; genome stability; histone chaperones; histone variants; oncohistones 1. Introduction In cell nuclei, the DNA assembles with histone proteins into chromatin. This highly organized nucleoprotein structure is a source of epigenetic information through modifications affecting the DNA, histone proteins, and variations in chromatin compaction states, which together regulate genome functions by dictating gene expression programs [1].
  • Recurrent Inversion Toggling and Great Ape Genome Evolution

    Recurrent Inversion Toggling and Great Ape Genome Evolution

    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Genet Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 December 15. Published in final edited form as: Nat Genet. 2020 August ; 52(8): 849–858. doi:10.1038/s41588-020-0646-x. Recurrent inversion toggling and great ape genome evolution David Porubsky1,2,9, Ashley D. Sanders3,9, Wolfram Höps3, PingHsun Hsieh1, Arvis Sulovari1, Ruiyang Li1, Ludovica Mercuri4, Melanie Sorensen1, Shwetha C. Murali1,5, David Gordon1,5, Stuart Cantsilieris1,6, Alex A. Pollen7, Mario Ventura4, Francesca Antonacci4, Tobias Marschall8, Jan O. Korbel3, Evan E. Eichler1,5,* 1Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. 2Max Planck Institute for Informatics, Saarland Informatics Campus E1.4, Saarbrücken, Germany. 3European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany. 4Dipartimento di Biologia, Università degli Studi di Bari “Aldo Moro”, Bari, Italy. 5Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA. 6Centre for Eye Research Australia, Department of Surgery (Ophthalmology), University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia. 7Department of Neurology, University of California, San Francisco (UCSF), San Francisco, California, USA. 8Institute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich Heine University Düsseldorf, Germany. 9These authors contributed equally to this work. Abstract Inversions play an important role in disease and evolution but are difficult to characterize because their breakpoints map to large repeats. We increased by six-fold the number (n = 1,069) of previously reported great ape inversions using Strand-seq and long-read sequencing. We find that the X chromosome is most enriched (2.5-fold) for inversions based on its size and duplication content.
  • Identification of Genetic Factors Underpinning Phenotypic Heterogeneity in Huntington’S Disease and Other Neurodegenerative Disorders

    Identification of Genetic Factors Underpinning Phenotypic Heterogeneity in Huntington’S Disease and Other Neurodegenerative Disorders

    Identification of genetic factors underpinning phenotypic heterogeneity in Huntington’s disease and other neurodegenerative disorders. By Dr Davina J Hensman Moss A thesis submitted to University College London for the degree of Doctor of Philosophy Department of Neurodegenerative Disease Institute of Neurology University College London (UCL) 2020 1 I, Davina Hensman Moss confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Collaborative work is also indicated in this thesis. Signature: Date: 2 Abstract Neurodegenerative diseases including Huntington’s disease (HD), the spinocerebellar ataxias and C9orf72 associated Amyotrophic Lateral Sclerosis / Frontotemporal dementia (ALS/FTD) do not present and progress in the same way in all patients. Instead there is phenotypic variability in age at onset, progression and symptoms. Understanding this variability is not only clinically valuable, but identification of the genetic factors underpinning this variability has the potential to highlight genes and pathways which may be amenable to therapeutic manipulation, hence help find drugs for these devastating and currently incurable diseases. Identification of genetic modifiers of neurodegenerative diseases is the overarching aim of this thesis. To identify genetic variants which modify disease progression it is first necessary to have a detailed characterization of the disease and its trajectory over time. In this thesis clinical data from the TRACK-HD studies, for which I collected data as a clinical fellow, was used to study disease progression over time in HD, and give subjects a progression score for subsequent analysis. In this thesis I show blood transcriptomic signatures of HD status and stage which parallel HD brain and overlap with Alzheimer’s disease brain.
  • A Genome Wide Screen in C. Elegans Identifies Cell Non-Autonomous Regulators of Oncogenic Ras Mediated Over-Proliferation DISSER

    A Genome Wide Screen in C. Elegans Identifies Cell Non-Autonomous Regulators of Oncogenic Ras Mediated Over-Proliferation DISSER

    A genome wide screen in C. elegans identifies cell non-autonomous regulators of oncogenic Ras mediated over-proliferation DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Komal Rambani Graduate Program in Biomedical Sciences The Ohio State University 2016 Dissertation Committee: Gustavo Leone, PhD “Advisor" Helen Chamberlin, PhD Gregory Lesinski, PhD Joanna Groden, PhD Jeffrey Parvin, PhD Thomas Ludwig, PhD Copyright by Komal Rambani 2016 ABSTRACT Coordinated proliferative signals from the mesenchymal cells play a crucial role in the regulation of proliferation of epithelial cells during normal development, wound healing and several other normal physiological conditions. However, when epithelial cells acquire a set of malignant mutations, they respond differently to these extrinsic proliferative signals elicited by the surrounding mesenchymal cells. This scenario leads to a pathological signaling microenvironment that enhances abnormal proliferation of mutant epithelial cells and hence tumor growth. Despite mounting evidence that mesenchymal (stromal) cells influence the growth of tumors and cancer progression, it is unclear which specific genes in the mesenchymal cells regulate the molecular signals that promote the over-proliferation of the adjacent mutant epithelial cells. We hypothesized that there are certain genes in the mesenchymal (stromal) cells that regulate proliferation of the adjacent mutant cells. The complexity of various stromal cell types and their interactions in vivo in cancer mouse models and human tumor samples limits our ability to identify mesenchymal genes important in this process. Thus, we took a cross-species approach to use C. elegans vulval development as a model to understand the impact of mesenchymal (mesodermal) cells on the proliferation of epithelial (epidermal) cells.
  • Genomic Mapping of the MHC Transactivator CIITA Using An

    Genomic Mapping of the MHC Transactivator CIITA Using An

    Wong et al. Genome Biology 2014, 15:494 http://genomebiology.com/2014/15/10/494 RESEARCH Open Access Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach Daniel Wong1†, Wanseon Lee1†, Peter Humburg1, Seiko Makino1, Evelyn Lau1, Vivek Naranbhai1, Benjamin P Fairfax1, Kenneth Chan2, Katharine Plant1 and Julian C Knight1* Abstract Background: The master transactivator CIITA is essential to the regulation of Major Histocompatibility Complex (MHC) class II genes and an effective immune response. CIITA is known to modulate a small number of non-MHC genes involved in antigen presentation such as CD74 and B2M but its broader genome-wide function and relationship with underlying genetic diversity has not been resolved. Results: We report the first genome-wide ChIP-seq map for CIITA and complement this by mapping inter-individual variation in CIITA expression as a quantitative trait. We analyse CIITA recruitment for pathophysiologically relevant primary human B cells and monocytes, resting and treated with interferon-gamma, in the context of the epigenomic regulatory landscape and DNA-binding proteins associated with the CIITA enhanceosome including RFX, CREB1/ATF1 and NFY. We confirm recruitment to proximal promoter sequences in MHC class II genes and more distally involving the canonical CIITA enhanceosome. Overall, we map 843 CIITA binding intervals involving 442 genes and find 95% of intervals are located outside the MHC and 60% not associated with RFX5 binding. Binding intervals are enriched for genes involved in immune function and infectious disease with novel loci including major histone gene clusters. We resolve differentially expressed genes associated in trans with a CIITA intronic sequence variant, integrate with CIITA recruitment and show how this is mediated by allele-specific recruitment of NF-kB.
  • The Human Canonical Core Histone Catalogue David Miguel Susano Pinto*, Andrew Flaus*,†

    The Human Canonical Core Histone Catalogue David Miguel Susano Pinto*, Andrew Flaus*,†

    bioRxiv preprint doi: https://doi.org/10.1101/720235; this version posted July 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. The Human Canonical Core Histone Catalogue David Miguel Susano Pinto*, Andrew Flaus*,† Abstract Core histone proteins H2A, H2B, H3, and H4 are encoded by a large family of genes dis- tributed across the human genome. Canonical core histones contribute the majority of proteins to bulk chromatin packaging, and are encoded in 4 clusters by 65 coding genes comprising 17 for H2A, 18 for H2B, 15 for H3, and 15 for H4, along with at least 17 total pseudogenes. The canonical core histone genes display coding variation that gives rise to 11 H2A, 15 H2B, 4 H3, and 2 H4 unique protein isoforms. Although histone proteins are highly conserved overall, these isoforms represent a surprising and seldom recognised variation with amino acid identity as low as 77 % between canonical histone proteins of the same type. The gene sequence and protein isoform diversity also exceeds com- monly used subtype designations such as H2A.1 and H3.1, and exists in parallel with the well-known specialisation of variant histone proteins. RNA sequencing of histone transcripts shows evidence for differential expression of histone genes but the functional significance of this variation has not yet been investigated. To assist understanding of the implications of histone gene and protein diversity we have catalogued the entire human canonical core histone gene and protein complement.
  • The Role of Histone Variants in the Epithelial-To-Mesenchymal Transition

    The Role of Histone Variants in the Epithelial-To-Mesenchymal Transition

    cells Review The Role of Histone Variants in the Epithelial-To-Mesenchymal Transition Imtiaz Nisar Lone 1, Burcu Sengez 1,2 , Ali Hamiche 3, Stefan Dimitrov 1,4 and Hani Alotaibi 1,2,* 1 Izmir Biomedicine and Genome Center, Izmir 35340, Turkey; [email protected] (I.N.L.); [email protected] (B.S.); [email protected] (S.D.) 2 Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir 35340, Turkey 3 Institute of Genetics and Molecular and Cellular Biology (IGBMC), 1 rue Laurent Fries, 67400 Illkirch, France; [email protected] 4 Université Grenoble Alpes, CNRS UMR 5309, INSERM U1209, Institute for Advanced Biosciences (IAB), Site Santé-Allée des Alpes, 38700 La Tronche, France * Correspondence: [email protected]; Tel.: +90-232-299-4100 (ext. 5071) Received: 18 October 2020; Accepted: 14 November 2020; Published: 17 November 2020 Abstract: The epithelial-to-mesenchymal transition (EMT) is a physiological process activated during early embryogenesis, which continues to shape tissues and organs later on. It is also hijacked by tumor cells during metastasis. The regulation of EMT has been the focus of many research groups culminating in the last few years and resulting in an elaborate transcriptional network buildup. However, the implication of epigenetic factors in the control of EMT is still in its infancy. Recent discoveries pointed out that histone variants, which are key epigenetic players, appear to be involved in EMT control. This review summarizes the available data on histone variants’ function in EMT that would contribute to a better understanding of EMT itself and EMT-related diseases.