DOCSLIB.ORG

SET1A/COMPASS and Shadow Enhancers in the Regulation of Homeotic Gene Expression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
SET1A/COMPASS and Shadow Enhancers in the Regulation of Homeotic Gene Expression Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press SET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expression Kaixiang Cao,1 Clayton K. Collings,1 Stacy A. Marshall,1 Marc A. Morgan,1 Emily J. Rendleman,1 Lu Wang,1 Christie C. Sze,1 Tianjiao Sun,1 Elizabeth T. Bartom,1 and Ali Shilatifard1,2 1Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA; 2Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA The homeotic (Hox) genes are highly conserved in metazoans, where they are required for various processes in de- velopment, and misregulation of their expression is associated with human cancer. In the developing embryo, Hox genes are activated sequentially in time and space according to their genomic position within Hox gene clusters. Accumulating evidence implicates both enhancer elements and noncoding RNAs in controlling this spatiotemporal expression of Hox genes, but disentangling their relative contributions is challenging. Here, we identify two cis- regulatory elements (E1 and E2) functioning as shadow enhancers to regulate the early expression of the HoxA genes. Simultaneous deletion of these shadow enhancers in embryonic stem cells leads to impaired activation of HoxA genes upon differentiation, while knockdown of a long noncoding RNA overlapping E1 has no detectable effect on their expression. Although MLL/COMPASS (complex of proteins associated with Set1) family of histone methyl- transferases is known to activate transcription of Hox genes in other contexts, we found that individual inactivation of the MLL1-4/COMPASS family members has little effect on early Hox gene activation. Instead, we demonstrate that SET1A/COMPASS is required for full transcriptional activation of multiple Hox genes but functions inde- pendently of the E1 and E2 cis-regulatory elements. Our results reveal multiple regulatory layers for Hox genes to fine-tune transcriptional programs essential for development. [Keywords: Hox genes; enhancer; COMPASS; SET1A; chromatin structure; epigenetic marks] Supplemental material is available for this article. Received December 15, 2016; revised version accepted April 12, 2017. In mammals, the 39 Hox genes, organized into four clus- Chromatin decondensation coincides with the activation ters on different chromosomes, encode helix–turn–helix sequences of HoxB and HoxD clusters during embryonic DNA-binding transcription factors (TFs) that are critical stem cell (ESC) differentiation and embryonic develop- for specifying the anterior–posterior body plan during an- ment (Chambeyron and Bickmore 2004; Chambeyron imal development (Alexander et al. 2009; Mallo et al. et al. 2005; Morey et al. 2007). The genome architecture 2010). Knockout experiments in mouse models indicate at the HoxD cluster is also dynamically remodeled at dif- that Hox genes are important for the development of the ferent development stages (Noordermeer et al. 2011, hindbrain, axial skeleton, and limbs (Wellik 2007; Zakany 2014). Moreover, multiple regulatory sequences are and Duboule 2007; Alexander et al. 2009). Hox genes in found to be critical for the activation of Hox clusters. each cluster are activated sequentially in both time and Retinoic acid (RA) response elements (RAREs) located space in the developing embryo according to their geno- at the 3′ of HoxA and HoxB clusters are responsible for mic position within the cluster (Kmita and Duboule the activation of 3′ Hox genes triggered by RA, but genet- 2003). Despite being extensively studied, the mechanisms ic studies and single-cell analyses suggest that additional underlying the spatial and temporal colinearity of Hox regulatory sequences are involved (Studer et al. 1994; genes remain mysterious. Popperl et al. 1995; Dupe et al. 1997; Maamar et al. Accumulating evidence demonstrates the impact of 2013). Indeed, a group of regulatory regions located cis-regulation on the activation of Hox gene clusters. © 2017 Cao et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publi- cation date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After Corresponding author: [email protected] six months, it is available under a Creative Commons License (At- Article published online ahead of print. Article and publication date are tribution-NonCommercial 4.0 International), as described at http://creati- online at http://www.genesdev.org/cgi/doi/10.1101/gad.294744.116. vecommons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 31:787–801 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/17; www.genesdev.org 787 Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Cao et al. >500 kb upstream of the HoxD cluster are necessary for formed RNA sequencing (RNA-seq) in undifferentiated the expression of 5′ HoxD genes in developing mouse and RA-treated ESCs at two different time points. Upon digits and genitals (Montavon et al. 2011; Lonfat et al. RA treatment, genes within the HoxA cluster, including 2014). On the other hand, distal enhancers downstream the lncRNA genes Halr1 and Hotairm1, were highly ele- from the HoxD cluster regulate the expression of 5′ vated, while the expression of Skap2, a neighboring gene HoxD genes in the forelimb (Andrey et al. 2013). Further- of the HoxA cluster, remained unchanged (Fig. 1A). En- more, DNA elements within the Hox gene clusters, hancers harboring RAREs contribute to the activation of which include CTCF-binding sites, have been shown to Hox genes (Studer et al. 1994; Frasch et al. 1995; Morrison serve as topological boundaries separating active and re- et al. 1996); however, deletion of the Hoxa1 proximal en- pressive domains during stem cell differentiation (Naren- hancer with RAREs significantly reduces, but does not si- dra et al. 2015). Nevertheless, distal regulatory elements lence, the expression of Hoxa1 in vivo (Dupe et al. 1997), required for the activation of the 3′ Hox genes are still suggesting the requirement of additional cis-regulatory se- unidentified. quences. To identify novel regulatory elements of HoxA Epigenetic mechanisms are associated with establish- genes, we performed ChIP-seq (chromatin immunoprecip- ing Hox gene expression patterns during embryonic itation [ChIP] combined with high-throughput sequenc- development and stem cell differentiation (Soshnikova ing) of the enhancer-associated histone marks H3K27ac and Duboule 2009). The antagonism between trithorax and H3K4me1 and the active promoter mark H3K4me3 group proteins (TrxG) and polycomb group (PcG) pro- in ESCs treated with RA. In addition to proximal enhanc- teins is known to enforce changes in H3K4me3 and ers of Hoxa1, two putative enhancer regions (referred to H3K27me3 levels at Hox clusters, resulting in activation here as E1 and E2), located in the gene desert between or repression, respectively, during development (Ring- Skap2 and Hoxa1, are enriched with H3K27ac upon RA rose and Paro 2004; Schuettengruber et al. 2007; Piunti treatment (Fig. 1B). These regions are marked initially and Shilatifard 2016). In mammals, the COMPASS (com- by H3K4me1 in undifferentiated ESCs, and, upon RA-in- plex of proteins associated with Set1) family of six pro- duced differentiation, this histone mark spreads to form tein complexes is responsible for the implementation of a broad domain covering the majority of the intergenic re- the vast majority of H3K4 methylation. The MLL1 gion (Fig. 1B). Additionally, moderate levels of H3K4me3 branch of the COMPASS family, which is related to Dro- were found at E1 upon differentiation (Fig. 1B). The E1 re- sophila Trx, is required for proper expression of many gion overlaps with the Halr1 gene; however, unlike the genes within the HoxA and HoxC clusters in mouse em- H3K4me3 peak that mainly covers the transcription start bryonic fibroblasts (MEFs) (Wang et al. 2009). MLL2 site (TSS) region, the H3K27ac-coated E1 is located within depletion in ESCs leads to loss of H3K4me3 at promoters the Halr1 gene body (Supplemental Fig. S1A). These data of bivalently marked genes, which includes the Hox suggest that E1 and E2 may gain enhancer activity upon genes, and at numerous intergenic regions bearing signa- RA induction and can potentially impact transcriptional tures of transcriptional enhancers (Hu et al. 2013b, 2017). activation of HoxA genes. Nevertheless, none of the members of the COMPASS Looping between enhancers and promoters plays an in- family has been demonstrated to participate in the early structive role in transcriptional activation (Deng et al. activation of anterior Hox genes during ESC differentia- 2012, 2014). To identify regions that gain interaction tion to date. with the HoxA cluster during RA-induced differentiation, To understand the relative contributions of cis-regula- we generated chromatin interaction profiles of the Hoxa1 tory sequences and the COMPASS family, we individually promoter in ESCs using circularized chromosome confor- and combinatorially examined the contribution of two mation capture (4C) combined with high-throughput se- shadow enhancers, a long noncoding RNA (lncRNA), quencing (4C-seq). Silent Hoxa1 interacts with the and members of the COMPASS family to early activation previously identified RARE-containing proximal enhanc- of HoxA genes during
Load more

Recommended publications
  • Genomic Analyses Reveal Foxg As an Upstream Regulator of Wnt1 Required For
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.08.416008; this version posted December 9, 2020. 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-NC-ND 4.0 International license. Genomic analyses reveal FoxG as an upstream regulator of wnt1 required for posterior identity specification in planarians E. Pascual-Carreras1, M. Marín-Barba3, S. Castillo-Lara1, P. Coronel-Córdoba1, M.S. Magri2, G.N. Wheeler3 J.F. Abril1, J.L. Gomez-Skarmeta2, E. Saló1* & T. Adell1* 1 Department of Genetics, Microbiology and Statistics, Universitat de Barcelona (UB) & Institute of Biomedicine of Universitat de Barcelona (IBUB), Barcelona, Spain. 2 Centro Andaluz de Biología del Desarollo (CABD), Universidad Pablo de Olavide, Sevilla, Spain. 3 School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, UK. *Corresponding authors: Emili Saló ([email protected]) and Teresa Adell ([email protected]) 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.08.416008; this version posted December 9, 2020. 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-NC-ND 4.0 International license. Abstract Embryonic specification of the first body axis requires the formation of an Organizer, a group of cells with the ability to instruct fates in the surrounding tissue. The existence of organizing regions in adults, i.e.
    [Show full text]
  • Epigenetic Mechanisms of Lncrnas Binding to Protein in Carcinogenesis
    cancers Review Epigenetic Mechanisms of LncRNAs Binding to Protein in Carcinogenesis Tae-Jin Shin, Kang-Hoon Lee and Je-Yoel Cho * Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul 08826, Korea; [email protected] (T.-J.S.); [email protected] (K.-H.L.) * Correspondence: [email protected]; Tel.: +82-02-800-1268 Received: 21 September 2020; Accepted: 9 October 2020; Published: 11 October 2020 Simple Summary: The functional analysis of lncRNA, which has recently been investigated in various fields of biological research, is critical to understanding the delicate control of cells and the occurrence of diseases. The interaction between proteins and lncRNA, which has been found to be a major mechanism, has been reported to play an important role in cancer development and progress. This review thus organized the lncRNAs and related proteins involved in the cancer process, from carcinogenesis to metastasis and resistance to chemotherapy, to better understand cancer and to further develop new treatments for it. This will provide a new perspective on clinical cancer diagnosis, prognosis, and treatment. Abstract: Epigenetic dysregulation is an important feature for cancer initiation and progression. Long non-coding RNAs (lncRNAs) are transcripts that stably present as RNA forms with no translated protein and have lengths larger than 200 nucleotides. LncRNA can epigenetically regulate either oncogenes or tumor suppressor genes. Nowadays, the combined research of lncRNA plus protein analysis is gaining more attention. LncRNA controls gene expression directly by binding to transcription factors of target genes and indirectly by complexing with other proteins to bind to target proteins and cause protein degradation, reduced protein stability, or interference with the binding of other proteins.
    [Show full text]
  • Bptf Is Essential for Murine Neocortical Development
    Bptf is essential for murine neocortical development Gerardo Zapata Thesis submitted to the Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirements for the Master’s degree in Biochemistry with specialization in Bioinformatics Department of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa © Gerardo Zapata, Ottawa, Canada, 2020 Abstract Chromatin remodeling complexes modulate DNA accessibility permitting neuronal progenitor cells to proliferate and differentiate to form the mammalian neocortex. In the case of BPTF (Bromodomain PHD transcription Factor), the major subunit of a chromatin remodelling complex called NURF (Nucleosome Remodelling Factor), mutations leading to its haploinsufficiency have been linked to cause a recently annotated human neurodevelopmental disorder called NEDDFL (Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies). Patients with this syndrome are mainly characterized with microcephaly and intellectual disability. We conditionally knockout (cKO) the Bptf gene during neocortical neurogenesis to analyze its role during embryonic and postnatal brain development. The Bptf cKO animals reveal significant forebrain hypoplasia. During cortical neurogenesis, the Bptf cKO mice show a reduction in intermediate neuronal progenitor (INP) cells, an increase in apoptosis as well as a prolonged cell cycle within proliferating progenitors. Similarly, the postmitotic pyramidal neurons of the Bptf cKO mice contained lower levels of Ctip2 and Foxp1. Lastly, our RNA-seq analysis delineated gene pathways deregulated by Bptf removal, which are involved in neurogenesis and neuronal differentiation. Our results indicate that Bptf is critical for murine telencephalon neurogenesis. The hypoplasia demonstrated in the mouse model can resemble the microcephaly displayed by the human NEDDFL patients, highlighting the relevance of chromatin remodelling complexes during intricate neural developmental processes.
    [Show full text]
  • Pointing the Finger
    RESEARCH HIGHLIGHTS Nature Reviews Molecular Cell Biology | AOP, published online 14 June 2006; doi:10.1038/nrm1966 DOI: 10.1038/nrm1966 URLs BPTF http://ca.expasy.org/uniprot/ Q9UIG2 ING2 http://ca.expasy.org/uniprot/ Q9ESK4 GENE EXPRESSION Pointing the finger Mechanistic links between specific histone-tail tumour suppressors, bound specifically to modifications and their effects on gene H3K4me3. ING2 is a subunit of a SIN3a–HDAC1 expression have been difficult to establish. histone-deacetylase complex. The authors However, four papers in Nature now identify the showed that in response to DNA damage, binding plant homeodomain (PHD) finger as an important of the ING2 PHD finger to H3K4me3 that is effector domain that binds to the trimethylated present at the promoters of actively transcribed K4 residue of histone H3 (H3K4me3) and couples proliferation genes enhanced the association of it to gene activation in one case and to gene the ING2–HDAC1 complex at these genes. This repression in another. resulted in increased histone-deacetylase activity Wysocka et al. affinity purified the BPTF and hence acute repression of the cognate (bromodomain and PHD finger transcription transcript. These findings, together with those of factor) subunit of NURF — an ATP-dependent Wysocka et al., indicate that PHD fingers have a chromatin remodelling complex — using an general role as effector domains that link H3K4me3-containing peptide. Mutational analysis H3K4me3 to diverse biological outcomes. narrowed the H3K4me3-interaction region to the The molecular mechanism that underlies the second, conserved bromodomain-proximal PHD recognition of H3K4me3 by the PHD finger of finger of BPTF. Knockdown of the histone ING2 was reported in a fourth linked paper.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Bioinformatics Analysis for the Identification of Differentially Expressed Genes and Related Signaling Pathways in H
    Bioinformatics analysis for the identification of differentially expressed genes and related signaling pathways in H. pylori-CagA transfected gastric cancer cells Dingyu Chen*, Chao Li, Yan Zhao, Jianjiang Zhou, Qinrong Wang and Yuan Xie* Key Laboratory of Endemic and Ethnic Diseases , Ministry of Education, Guizhou Medical University, Guiyang, China * These authors contributed equally to this work. ABSTRACT Aim. Helicobacter pylori cytotoxin-associated protein A (CagA) is an important vir- ulence factor known to induce gastric cancer development. However, the cause and the underlying molecular events of CagA induction remain unclear. Here, we applied integrated bioinformatics to identify the key genes involved in the process of CagA- induced gastric epithelial cell inflammation and can ceration to comprehend the potential molecular mechanisms involved. Materials and Methods. AGS cells were transected with pcDNA3.1 and pcDNA3.1::CagA for 24 h. The transfected cells were subjected to transcriptome sequencing to obtain the expressed genes. Differentially expressed genes (DEG) with adjusted P value < 0.05, | logFC |> 2 were screened, and the R package was applied for gene ontology (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The differential gene protein–protein interaction (PPI) network was constructed using the STRING Cytoscape application, which conducted visual analysis to create the key function networks and identify the key genes. Next, the Submitted 20 August 2020 Kaplan–Meier plotter survival analysis tool was employed to analyze the survival of the Accepted 11 March 2021 key genes derived from the PPI network. Further analysis of the key gene expressions Published 15 April 2021 in gastric cancer and normal tissues were performed based on The Cancer Genome Corresponding author Atlas (TCGA) database and RT-qPCR verification.
    [Show full text]
  • The ISWI Chromatin Remodelling Factor NURF Is Not Required for Mitotic
    1/26/2021 - Open Access The ISWI chromatin remodelling factor NURF is not required for mitotic male X chromosome organisation So Yeon Kwon1§*, Boyun Jang1* and Paul Badenhorst1§ 1Birmingham Centre for Genome Biology and Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom §To whom correspondence should be addressed: [email protected]; [email protected] *These authors contributed equally. Abstract The nucleosome remodelling factor (NURF) is an ISWI-class ATP-dependent chromatin remodeling enzyme required both for gene expression and higher order chromatin organisation. NURF binds to histone modifications that decorate the Drosophila polytene male X chromosome and is required to maintain correct organisation of this chromosome. NURF mutants exhibit distorted and decondensed polytene male X chromosomes dependent on the presence of the male-specific lethal (MSL) complex. Here we tested whether mitotic chromosomes similarly require NURF to maintain correct morphology. Surprisingly, although the MSL complex remains associated with mitotic male X chromosomes, NURF is not required to maintain morphology. While the ISWI subunit of NURF is known to remain associated with mitotic chromosomes we show that the NURF specificity subunit Nurf301/BPTF dissociates from chromatin during both Drosophila and human mitosis, further illuminating that NURF is dispensable for mitotic chromosome organisation. Figure 1. The chromatin remodelling factor NURF is not required for mitotic chromosome cohesion, condensation or X chromosome morphology: A) Mutation of either the NURF specificity subunit Nurf301 or the NURF catalytic subunit Iswi does not disrupt male X chromosome morphology or result in loss of sister chromatid cohesion.
    [Show full text]
  • Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation
    fnmol-14-680280 June 30, 2021 Time: 16:59 # 1 ORIGINAL RESEARCH published: 06 July 2021 doi: 10.3389/fnmol.2021.680280 Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation Laura R. Goodwin1,2, Gerardo Zapata1,2, Sara Timpano1, Jacob Marenger1 and David J. Picketts1,2,3* 1 Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada, 2 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada, 3 Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada Chromatin remodeling proteins utilize the energy from ATP hydrolysis to mobilize Edited by: nucleosomes often creating accessibility for transcription factors within gene regulatory Veronica Martinez Cerdeño, University of California, Davis, elements. Aberrant chromatin remodeling has diverse effects on neuroprogenitor United States homeostasis altering progenitor competence, proliferation, survival, or cell fate. Previous Reviewed by: work has shown that inactivation of the ISWI genes, Smarca5 (encoding Snf2h) and Mitsuhiro Hashimoto, Fukushima Medical University, Japan Smarca1 (encoding Snf2l) have dramatic effects on brain development. Smarca5 Koji Shibasaki, conditional knockout mice have reduced progenitor expansion and severe forebrain Nagasaki University, Japan hypoplasia, with a similar effect on the postnatal growth of the cerebellum. In contrast, *Correspondence: Smarca1 mutants exhibited enlarged forebrains
    [Show full text]
  • The Genomics of Ecological Flexibility, Large Brains, and Long Lives in Capuchin Monkeys Revealed with Fe- Calfacs,” by Joseph D
    Correction ANTHROPOLOGY Correction for “The genomics of ecological flexibility, large brains, and long lives in capuchin monkeys revealed with fe- calFACS,” by Joseph D. Orkin, Michael J. Montague, Daniela Tejada-Martinez, Marc de Manuel, Javier del Campo, Saul Cheves Hernandez, Anthony Di Fiore, Claudia Fontsere, Jason A. Hodgson, Mareike C. Janiak, Lukas F. K. Kuderna, Esther Lizano, Maria Pia Martin, Yoshihito Niimura, George H. Perry, Carmen Soto Valverde, Jia Tang, Wesley C. Warren, João Pedro de Magalhães, Shoji Kawamura, Tomàs Marquès-Bonet, Roman Krawetz, and Amanda D. Melin, which published February 11, 2021; 10.1073/ pnas.2010632118 (Proc. Natl. Acad. Sci. U.S.A. 118, e2010632118). The authors note that Fig. 4 in this article uses previously published silhouette images for depicted species. This Correction updates the caption to reflect the necessary credit lines for the material reused. The updated caption is: “Genes under positive selection in white-faced capuchin monkeys show enrichment associated with longevity (maximum recorded lifespan in cap- tivity) and brain size and development. Several genes showing evidence of positive selection in the Cebus lineage are listed for CORRECTION each trait. The displayed species are the primates used for the PAML run, or a congeneric species in cases of missing trait data (e.g., C. capucinus in place of C. imitator). Relative brain size, calculated as EQ = brain mass/(0.085 × (body mass0.775)) (1), is displayed to account for the large range in body mass. Trait data are from refs. 1, 8, 109, and 110. Cebus capucinus silhouette credit: Phylopic/Sarah Werning, licensed under CC BY 3.0.
    [Show full text]
  • Positional Specificity of Different Transcription Factor Classes Within Enhancers
    Positional specificity of different transcription factor classes within enhancers Sharon R. Grossmana,b,c, Jesse Engreitza, John P. Raya, Tung H. Nguyena, Nir Hacohena,d, and Eric S. Landera,b,e,1 aBroad Institute of MIT and Harvard, Cambridge, MA 02142; bDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; cProgram in Health Sciences and Technology, Harvard Medical School, Boston, MA 02215; dCancer Research, Massachusetts General Hospital, Boston, MA 02114; and eDepartment of Systems Biology, Harvard Medical School, Boston, MA 02215 Contributed by Eric S. Lander, June 19, 2018 (sent for review March 26, 2018; reviewed by Gioacchino Natoli and Alexander Stark) Gene expression is controlled by sequence-specific transcription type-restricted enhancers (active in <50% of the cell types) and factors (TFs), which bind to regulatory sequences in DNA. TF ubiquitous enhancers (active in >90% of the cell types) (SI Ap- binding occurs in nucleosome-depleted regions of DNA (NDRs), pendix, Fig. S1C). which generally encompass regions with lengths similar to those We next sought to infer functional TF-binding sites within the protected by nucleosomes. However, less is known about where active regulatory elements. In a recent study (5), we found that within these regions specific TFs tend to be found. Here, we char- TF binding is strongly correlated with the quantitative DNA acterize the positional bias of inferred binding sites for 103 TFs accessibility of a region. Furthermore, the TF motifs associated within ∼500,000 NDRs across 47 cell types. We find that distinct with enhancer activity in reporter assays in a cell type corre- classes of TFs display different binding preferences: Some tend to sponded closely to those that are most enriched in the genomic have binding sites toward the edges, some toward the center, and sequences of active regulatory elements in that cell type (5).
    [Show full text]
  • Positional Specificity of Different Transcription Factor Classes Within Enhancers
    Positional specificity of different transcription factor classes within enhancers Sharon R. Grossmana,b,c, Jesse Engreitza, John P. Raya, Tung H. Nguyena, Nir Hacohena,d, and Eric S. Landera,b,e,1 aBroad Institute of MIT and Harvard, Cambridge, MA 02142; bDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; cProgram in Health Sciences and Technology, Harvard Medical School, Boston, MA 02215; dCancer Research, Massachusetts General Hospital, Boston, MA 02114; and eDepartment of Systems Biology, Harvard Medical School, Boston, MA 02215 Contributed by Eric S. Lander, June 19, 2018 (sent for review March 26, 2018; reviewed by Gioacchino Natoli and Alexander Stark) Gene expression is controlled by sequence-specific transcription type-restricted enhancers (active in <50% of the cell types) and factors (TFs), which bind to regulatory sequences in DNA. TF ubiquitous enhancers (active in >90% of the cell types) (SI Ap- binding occurs in nucleosome-depleted regions of DNA (NDRs), pendix, Fig. S1C). which generally encompass regions with lengths similar to those We next sought to infer functional TF-binding sites within the protected by nucleosomes. However, less is known about where active regulatory elements. In a recent study (5), we found that within these regions specific TFs tend to be found. Here, we char- TF binding is strongly correlated with the quantitative DNA acterize the positional bias of inferred binding sites for 103 TFs accessibility of a region. Furthermore, the TF motifs associated within ∼500,000 NDRs across 47 cell types. We find that distinct with enhancer activity in reporter assays in a cell type corre- classes of TFs display different binding preferences: Some tend to sponded closely to those that are most enriched in the genomic have binding sites toward the edges, some toward the center, and sequences of active regulatory elements in that cell type (5).
    [Show full text]
  • Inphernet Provides Attractive Monogenic Disease Gene Hypotheses Using Patient Genes Indirect Neighbors
    medRxiv preprint doi: https://doi.org/10.1101/2020.07.10.20150425; this version posted July 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Title InpherNet provides attractive monogenic disease gene hypotheses using patient genes indirect neighbors Authors Boyoung Yoo1, Johannes Birgmeier1, Jonathan A. Bernstein2, Gill Bejerano1,2,3,4,* Affiliations 1 Department of Computer Science, Stanford School of Engineering, Stanford, California 94305, USA 2 Department of Pediatrics, Stanford School of Medicine, Stanford, California 94305, USA 3 Department of Developmental Biology, Stanford School of Medicine, Stanford, California 94305, USA 4 Department of Biomedical Data Science, Stanford School of Medicine, Stanford, California 94305, USA Corresponding Author *Gill Bejerano [email protected] Stanford University Stanford, CA 94305 1 (650) 725-6792 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.07.10.20150425; this version posted July 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Abstract Close to 70% of patients suspected to have a Mendelian disease remain undiagnosed after genome sequencing, partly because our current knowledge about disease-causing genes is incomplete.
    [Show full text]