DOCSLIB.ORG

Stem Cell Differentiation As a Many-Body Problem

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Stem Cell Differentiation As a Many-Body Problem Stem cell differentiation as a many-body problem Bin Zhanga,b and Peter G. Wolynesa,b,c,1 Departments of aChemistry and cPhysics and Astronomy, and bCenter for Theoretical Biological Physics, Rice University, Houston, TX 77005 Contributed by Peter G. Wolynes, May 9, 2014 (sent for review March 25, 2014) Stem cell differentiation has been viewed as coming from transitions transcription factors function as pioneers that can directly bind between attractors on an epigenetic landscape that governs the with the chromatin sites occupied by the nucleosome, slow dynamics of a regulatory network involving many genes. Rigorous DNA binding (14, 15) is still a good approximation to describe definition of such a landscape is made possible by the realization the effect of the progressive change of the chromatin structure that gene regulation is stochastic, owing to the small copy number of and histone modification induced by the pioneer factors on gene the transcription factors that regulate gene expression and because regulation (16). As a result, DNA binding must be treated on of the single-molecule nature of the gene itself. We develop an ap- equal footing together with protein synthesis and degradation proximation that allows the quantitative construction of the epige- to fully understand eukaryotic gene regulation (14–18). netic landscape for large realistic model networks. Applying this By increasing the dimensionality of the problem, investigating approach to the network for embryonic stem cell development ex- the effects arising from slow DNA-binding kinetics on gene net- plains many experimental observations, including the heteroge- work dynamics becomes computationally challenging. Although neous distribution of the transcription factor Nanog and its role in being in some aspects conceptually transparent, where one can safeguarding the stem cell pluripotency, which can be understood directly simulate the chemical reactions involved in a gene network by finding stable steady-state attractors and the most probable using a Monte Carlo algorithm (19), such a procedure quickly transition paths between those attractors. We also demonstrate becomes inefficient as the system complexity increases and is even that the switching rate between attractors can be significantly impractical for studying rare, transient switching events between influenced by the gene expression noise arising from the fluctua- steady states that occur on long timescales. In recognizing the close tions of DNA occupancy when binding to a specific DNA site is slow. analogy between gene networks and magnetic systems, Sasai and Wolynes suggested that analytical approaches originating from gene network | most probable path | master equation quantum statistical mechanics could be used to study the epigenetic landscape of networks and discussed the steady states of a very nderstanding the underlying mechanisms of the differenti- stylized model network with many attractors (4). Although their Uation of stem cells into many distinct cell types has long been approach was efficient in identifying steady-state solutions, it re- a goal of developmental biology (1) and regenerative medicine (2). mained to show how this approach can characterize transitions The epigenetic landscape, originally proposed by Waddington, has between different attractors. In the adiabatic limit where DNA proved to be a useful metaphor for visualizing cellular dynamics (3). binding is fast, analytical approaches to the transition process based However, is it more than a metaphor? In this view, cell phenotypes on large deviation theory have proved successful in studying noise- are identified as attractors with well-defined patterns of robust gene induced transitions (7, 20–22). Here we show how to find equiva- expression, and differentiation occurs through transitions from the lent approaches for large networks where DNA binding must be stem cell attractor to other attractors for the differentiated cells. It treated explicitly. has become clear that for simple models, taking into account sto- In this paper, we generalize a kinetic model originally pro- chastic effects allows a well-defined landscape to be constructed posed by Sasai and Wolynes (4) to explicitly model DNA binding (4–6). This generalized potential landscape governs much of the along with protein synthesis and degradation in large gene net- gene regulatory network dynamics, such that corrections to such works with multifactorial and complex switches. An approxima- a landscape picture can also be defined and formalized (7, 8). It tion method is further developed that allows the construction of remains a challenge to construct such landscapes for realistically large network models. Significance Describing the stochastic dynamics of gene networks must include the statistics of synthesizing transcription factors, their A molecular understanding of stem cell differentiation requires degradation, and their binding to genes on the DNA. These all the study of gene regulatory network dynamics that includes play crucial roles in shaping the epigenetic landscape (9). Due to the statistics of synthesizing transcription factors, their deg- the complexity of the assembly of the machinery involved for radation, and their binding to the DNA. Brute force simulation protein synthesis, it has often been assumed that protein trans- for complex large realistic networks can be computationally lation is much slower than the diffusion-limited DNA-binding challenging. Here we develop a sound approximation method process. Under this view, the ensemble of DNA occupancies, i.e., ’ built upon theories originating from quantum statistical me- the set of transcription factors bound at a gene s regulatory ele- chanics to study the network for embryonic stem cell de- ments, can be assumed to have achieved a quasi-equilibrium so that velopment. Mechanistic insight is provided on the role of the the expression dynamics of this gene can then be described as a – master regulator Nanog in safeguarding stem cell pluripotency. birth death process governed by an averaged protein production We also demonstrate the significant influence of DNA-binding rate that depends nonlinearly on transcription factor concen- kinetics, an aspect that often has been overlooked, on the BIOPHYSICS AND trations (10). Although perhaps valid for some networks in pro- transition rate between gene network steady states. COMPUTATIONAL BIOLOGY karyotic cells, this assumption on timescales is probably not completely adequate for eukaryotic systems because the pro- Author contributions: B.Z. and P.G.W. designed research, performed research, analyzed cesses of chromatin decondensation and unwrapping of DNA data, and wrote the paper. from nucleosomes, both of which are required for proteins to bind, The authors declare no conflict of interest. take time. The high-level architecture of chromatin can severely Freely available online through the PNAS open access option. limit the access of transcription factors to the DNA, slowing down 1To whom correspondence should be addressed. E-mail: [email protected]. CHEMISTRY DNA-binding kinetics (11, 12) and resulting in gene expres- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. sion noise deviating from Poisson statistics (13). Even when the 1073/pnas.1408561111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1408561111 PNAS | July 15, 2014 | vol. 111 | no. 28 | 10185–10190 Downloaded by guest on September 27, 2021 the network’s epigenetic landscape via the determination of not A Oct4 Oct4 only steady-state solutions, but also most probable transition OCT4 CDX2 paths and stochastic switching rates between steady states. When k applied to a model of the core transcriptional regulatory network h Oct4 Oct4 of embryonic stem cells, these approximations turn out to explain g Regulatory Oct4 Oct4 the observed fluctuations in the expression of the master plu- Element f Cdx2 Gene ripotent regulator Nanog and the important role it has in safe- Cdx2 Cdx2 guarding stem cell pluripotency against differentiation. We also Oct4 Gene f Regulatory g Element demonstrate the striking effect that DNA-binding kinetics have Cdx2 h Cdx2 on the switching rate between steady states, making clear the Cdx2 Cdx2 importance of explicitly modeling fluctuations of DNA occu- k pancy in studying the fate of gene networks. Theoretical Approaches for Gene Networks B Viewed as a molecular process, gene regulation is complicated, GCNF with many actors as well as attractors, and spans a large spatial GATA6 CDX2 and temporal domain. Several approximations are needed to make tractable mathematical models. We use an admittedly simplified model but one that contains many of the crucial fea- Activation tures of the real embryonic stem cell network. Repression KLF4 PBX1 Pluripotency NANOG Constructing Schematic Kinetic Models for Gene Networks. Following Sasai and Wolynes (4), we model gene regulation at a level that Differentiation includes explicit binding and unbinding of transcription factors to OCT4 SOX2 the DNA, protein translation, and protein degradation. Both the mRNA intermediary and the serial nature of macromolecular Oct4-Sox2 synthesis are neglected in the present model but are likely im- portant. Fig. 1A illustrates how we can diagram a mutual re- pression motif between genes Cdx2 and Oct4. The gene Cdx2 Fig. 1. A schematic gene regulatory network for the embryonic stem cell. can be transcribed to proteins at a rate g, which will change (A) Schematics
Load more

Recommended publications
  • GABPA Is a Master Regulator of Luminal Identity and Restrains Aggressive Diseases in Bladder Cancer
    Cell Death & Differentiation (2020) 27:1862–1877 https://doi.org/10.1038/s41418-019-0466-7 ARTICLE GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer 1,2,3 3,4 5 2,5 5 3 5 5 Yanxia Guo ● Xiaotian Yuan ● Kailin Li ● Mingkai Dai ● Lu Zhang ● Yujiao Wu ● Chao Sun ● Yuan Chen ● 5 6 3 1,2 1,2 3,7 Guanghui Cheng ● Cheng Liu ● Klas Strååt ● Feng Kong ● Shengtian Zhao ● Magnus Bjorkhölm ● Dawei Xu 3,7 Received: 3 June 2019 / Revised: 20 November 2019 / Accepted: 21 November 2019 / Published online: 4 December 2019 © The Author(s) 2019. This article is published with open access Abstract TERT promoter mutations occur in the majority of glioblastoma, bladder cancer (BC), and other malignancies while the ETS family transcription factors GABPA and its partner GABPB1 activate the mutant TERT promoter and telomerase in these tumors. GABPA depletion or the disruption of the GABPA/GABPB1 complex by knocking down GABPB1 was shown to inhibit telomerase, thereby eliminating the tumorigenic potential of glioblastoma cells. GABPA/B1 is thus suggested as a cancer therapeutic target. However, it is unclear about its role in BC. Here we unexpectedly observed that GABPA ablation 1234567890();,: 1234567890();,: inhibited TERT expression, but robustly increased proliferation, stem, and invasive phenotypes and cisplatin resistance in BC cells, while its overexpression exhibited opposite effects, and inhibited in vivo metastasizing in a xenograft transplant model. Mechanistically, GABPA directly activates the transcription of FoxA1 and GATA3, key transcription factors driving luminal differentiation of urothelial cells. Consistently, TCGA/GEO dataset analyses show that GABPA expression is correlated positively with luminal while negatively with basal signatures.
    [Show full text]
  • Transcription Factor SPZ1 Promotes TWIST-Mediated Epithelial–Mesenchymal Transition and Oncogenesis in Human Liver Cancer
    OPEN Oncogene (2017) 36, 4405–4414 www.nature.com/onc ORIGINAL ARTICLE Transcription factor SPZ1 promotes TWIST-mediated epithelial–mesenchymal transition and oncogenesis in human liver cancer L-T Wang1, S-S Chiou2,3, C-Y Chai4, E Hsi5, C-M Chiang6, S-K Huang7, S-N Wang8,9, KK Yokoyama1,10,11,12,13,14 and S-H Hsu1,12 The epithelial–mesenchymal transition (EMT) is an important process in the progression of cancer. However, its occurrence and mechanism of regulation are not fully understood. We propose a regulatory pathway in which spermatogenic leucine zipper 1 (SPZ1) promotes EMT through its transactivating ability in increasing TWIST1 expression. We compared the expression of SPZ1 and TWIST1 in specimens of hepatocarcinoma cells (HCCs) and non-HCCs. Expression of SPZ1 exhibited a tumor-specific expression pattern and a high correlation with patients’ survival time, tumor size, tumor number and progression stage. Moreover, forced expression and knockdown of SPZ1 in hepatoma cells showed that SPZ1 was able to regulate the cellular proliferation, invasion, and tumorigenic activity in a TWIST1-dependent manner in vitro and in vivo. These data demonstrate that SPZ1, a newly dscribed molecule, transactivates TWIST1 promoters, and that this SPZ1-TWIST axis mediates EMT signaling and exerts significant regulatory effects on tumor oncogenesis. Oncogene (2017) 36, 4405–4414; doi:10.1038/onc.2017.69; published online 3 April 2017 INTRODUCTION by phosphorylation, which results in SPZ1 translocation into the Despite the identification of potential oncogenic drivers and their nucleus and activation of downstream gene expression such as 16 roles as master regulators of cancer initiation, the underlying the proliferating cell nuclear antigen.
    [Show full text]
  • Development, Maintenance and Functions of CD8+ T-Regulatory Cells
    Chakraborty S, Sa G. J Immunol Sci. (2018); 2(2): 8-12 Journal of Immunological Sciences Minireview Open Access Development, maintenance and functions of CD8+ T-regulatory cells: Molecular orchestration of FOXP3 transcription Sreeparna Chakraborty1 & Gaurisankar Sa1* 1Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700054, India Article Info ABSTRACT Article Notes Modulation of immune cells to rejuvenate the immune responses Received: January 10, 2018 against cancer becomes a promising strategy for cancer therapy. T-regulatory Accepted: March 23, 2018 cells are one of the major hurdles in successful cancer immunotherapy. Recent + + *Correspondence: studies discovered that apart from CD4 Treg cells, CD8 Tregs also play roles in Prof. Gaurisankar Sa, Division of Molecular Medicine, Bose tumor immune evasion. Moreover, CD8+ Tregs shows synergistic immunosup- Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, pression with CD4+ Treg cells in tumor microenvironment. Several phenotypic Kolkata 700 054, India; markers have been described for peripherally induced CD8+ Treg cells, but Tel: +91-33-2569-3258; till now no universal phenotypic signature has yet established. FOXP3 is the Fax: +91-33-2355-3886, E-mail: [email protected] master regulator of Treg cells and its transcription is critically regulated by pro- © 2018 Sa G. This article is distributed under the terms of the moter region as well as three intronic conserved non-coding regions, viz; CNS Creative Commons Attribution 4.0 International License. 1, 2 and 3. In this review, we have described the transcriptional networking associated with the regulation of FOXP3 in tumor-CD8+ Treg cells along with Keywords: CD4+ nTreg and iTreg cells.
    [Show full text]
  • Nanog-Like Regulates Endoderm Formation Through the Mxtx2-Nodal Pathway
    Nanog-like Regulates Endoderm Formation through the Mxtx2-Nodal Pathway The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Xu, Cong, Zi Peng Fan, Patrick Muller, Rachel Fogley, Anthony DiBiase, Eirini Trompouki, Juli Unternaehrer, et al. “Nanog-Like Regulates Endoderm Formation through the Mxtx2-Nodal Pathway.” Developmental Cell 22, no. 3 (March 2012): 625–638. © 2012 Elsevier Inc. As Published http://dx.doi.org/10.1016/j.devcel.2012.01.003 Publisher Elsevier Version Final published version Citable link http://hdl.handle.net/1721.1/91520 Terms of Use Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. Developmental Cell Article Nanog-like Regulates Endoderm Formation through the Mxtx2-Nodal Pathway Cong Xu,1,2 Zi Peng Fan,3 Patrick Mu¨ller,4 Rachel Fogley,1 Anthony DiBiase,1,2 Eirini Trompouki,1,2 Juli Unternaehrer,1,2 Fengzhu Xiong,5 Ingrid Torregroza,6 Todd Evans,6 Sean G. Megason,5 George Q. Daley,1,2 Alexander F. Schier,4 Richard A. Young,3 and Leonard I. Zon1,2,* 1Howard Hughes Medical Institute 2Division of Hematology/Oncology Children’s Hospital Boston and Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA 3Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA 4Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA 5Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA 6Department of Surgery, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA *Correspondence: [email protected] DOI 10.1016/j.devcel.2012.01.003 SUMMARY required for acquisition of the pluripotent ground state in both embryonic development and somatic cell reprogramming (Silva In mammalian embryonic stem cells, the acquisition et al., 2009).
    [Show full text]
  • POU2F3 Is a Master Regulator of a Tuft Cell-Like Variant of Small Cell Lung Cancer
    Downloaded from genesdev.cshlp.org on October 9, 2021 - Published by Cold Spring Harbor Laboratory Press POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer Yu-Han Huang,1 Olaf Klingbeil,1 Xue-Yan He,1 Xiaoli S. Wu,1,2 Gayatri Arun,1 Bin Lu,1 Tim D.D. Somerville,1 Joseph P. Milazzo,1 John E. Wilkinson,3 Osama E. Demerdash,1 David L. Spector,1 Mikala Egeblad,1 Junwei Shi,4 and Christopher R. Vakoc1 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 2Genetics Program, Stony Brook University, Stony Brook, New York 11794, USA; 3Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA; 4Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expres- sion of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells. Using chromatin- and RNA-profiling experiments, we provide evidence that POU2F3 is a master regulator of tuft cell identity in a variant form of SCLC.
    [Show full text]
  • Master Regulator Analysis of Paragangliomas Carrying Sdhx, VHL,Or MAML3 Genetic Alterations John A
    Smestad and Maher BMC Cancer (2019) 19:619 https://doi.org/10.1186/s12885-019-5813-z RESEARCHARTICLE Open Access Master regulator analysis of paragangliomas carrying SDHx, VHL,or MAML3 genetic alterations John A. Smestad1,2 and L. James Maher III2* Abstract Background: Succinate dehydrogenase (SDH) loss and mastermind-like 3 (MAML3) translocation are two clinically important genetic alterations that correlate with increased rates of metastasis in subtypes of human paraganglioma and pheochromocytoma (PPGL) neuroendocrine tumors. Although hypotheses propose that succinate accumulation after SDH loss poisons dioxygenases and activates pseudohypoxia and epigenomic hypermethylation, it remains unclear whether these mechanisms account for oncogenic transcriptional patterns. Additionally, MAML3 translocation has recently been identified as a genetic alteration in PPGL, but is poorly understood. We hypothesize that a key to understanding tumorigenesis driven by these genetic alterations is identification of the transcription factors responsible for the observed oncogenic transcriptional changes. Methods: We leverage publicly-available human tumor gene expression profiling experiments (N = 179) to reconstruct a PPGL tumor-specific transcriptional network. We subsequently use the inferred transcriptional network to perform master regulator analyses nominating transcription factors predicted to control oncogenic transcription in specific PPGL molecular subtypes. Results are validated by analysis of an independent collection of PPGL tumor specimens (N = 188). We then perform a similar master regulator analysis in SDH-loss mouse embryonic fibroblasts (MEFs) to infer aspects of SDH loss master regulator response conserved across species and tissue types. Results: A small number of master regulator transcription factors are predicted to drive the observed subtype- specific gene expression patterns in SDH loss and MAML3 translocation-positive PPGL.
    [Show full text]
  • The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis
    International Journal of Molecular Sciences Review The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis Eunjeong Kang † , Jihye Seo † , Haelim Yoon and Sayeon Cho * Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea; [email protected] (E.K.); [email protected] (J.S.); [email protected] (H.Y.) * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Epithelial–mesenchymal transition (EMT) is generally observed in normal embryogenesis and wound healing. However, this process can occur in cancer cells and lead to metastasis. The contribution of EMT in both development and pathology has been studied widely. This transition requires the up- and down-regulation of specific proteins, both of which are regulated by EMT- inducing transcription factors (EMT-TFs), mainly represented by the families of Snail, Twist, and ZEB proteins. This review highlights the roles of key EMT-TFs and their post-translational regulation in cancer metastasis. Keywords: metastasis; epithelial–mesenchymal transition; transcription factor; Snail; Twist; ZEB Citation: Kang, E.; Seo, J.; Yoon, H.; 1. Introduction Cho, S. The Post-Translational Morphological alteration in tissues is related to phenotypic changes in cells [1]. Regulation of Changes in morphology and functions of cells can be caused by changes in transcrip- Epithelial–Mesenchymal tional programs and protein expression [2]. One such change is epithelial–mesenchymal Transition-Inducing Transcription transition (EMT). Factors in Cancer Metastasis. Int. J. EMT is a natural trans-differentiation program of epithelial cells into mesenchymal Mol. Sci. 2021, 22, 3591. https:// cells [2]. EMT is primarily related to normal embryogenesis, including gastrulation, renal doi.org/10.3390/ijms22073591 development, formation of the neural crest, and heart development [3].
    [Show full text]
  • MITF: Master Regulator of Melanocyte Development and Melanoma Oncogene
    Review TRENDS in Molecular Medicine Vol.12 No.9 MITF: master regulator of melanocyte development and melanoma oncogene Carmit Levy, Mehdi Khaled and David E. Fisher Melanoma Program and Department of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, 44 Binney Street, Boston, MA 02115, USA Microphthalmia-associated transcription factor (MITF) between MITF and TFE3 in the development of the acts as a master regulator of melanocyte development, osteoclast lineage [8]. From these analyses, it seems that function and survival by modulating various differentia- MITF is the only MiT family member that is functionally tion and cell-cycle progression genes. It has been essential for normal melanocytic development. demonstrated that MITF is an amplified oncogene in a MITF is thought to mediate significant differentiation fraction of human melanomas and that it also has an effects of the a-melanocyte-stimulating hormone (a-MSH) oncogenic role in human clear cell sarcoma. However, [9,10] by transcriptionally regulating enzymes that are MITF also modulates the state of melanocyte differentia- essential for melanin production in differentiated melano- tion. Several closely related transcription factors also cytes [11]. Although these data implicate MITF in both the function as translocated oncogenes in various human survival and differentiation of melanocytes, little is known malignancies. These data place MITF between instruct- about the biochemical regulatory pathways that control ing melanocytes towards terminal differentiation and/or MITF in its different roles. pigmentation and, alternatively, promoting malignant behavior. In this review, we survey the roles of MITF as a Transcriptional and post-translational MITF regulation master lineage regulator in melanocyte development The MITF gene has a multi-promoter organization in and its emerging activities in malignancy.
    [Show full text]
  • Computational Identification of Master Regulators Influencing
    International Journal of Molecular Sciences Article Computational Identification of Master Regulators Influencing Trypanotolerance in Cattle Abirami Rajavel 1 , Armin Otto Schmitt 1,2 and Mehmet Gültas 1,2,∗ 1 Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; [email protected] (A.R.); [email protected] (A.O.S.) 2 Center for Integrated Breeding Research (CiBreed), Albrecht-Thaer-Weg 3, Georg-August University, 37075 Göttingen, Germany * Correspondence: [email protected] Abstract: African Animal Trypanosomiasis (AAT) is transmitted by the tsetse fly which carries pathogenic trypanosomes in its saliva, thus causing debilitating infection to livestock health. As the disease advances, a multistage progression process is observed based on the progressive clinical signs displayed in the host’s body. Investigation of genes expressed with regular monotonic patterns (known as Monotonically Expressed Genes (MEGs)) and of their master regulators can provide important clue for the understanding of the molecular mechanisms underlying the AAT disease. For this purpose, we analysed MEGs for three tissues (liver, spleen and lymph node) of two cattle breeds, namely trypanosusceptible Boran and trypanotolerant N’Dama. Our analysis revealed cattle breed-specific master regulators which are highly related to distinguish the genetic programs in both cattle breeds. Especially the master regulators MYC and DBP found in this study, seem to influence the immune responses strongly, thereby susceptibility and trypanotolerance of Boran and N’Dama respectively. Furthermore, our pathway analysis also bolsters the crucial roles of these master regulators. Taken together, our findings provide novel insights into breed-specific master regulators which orchestrate the regulatory cascades influencing the level of trypanotolerance in cattle breeds and thus could be promising drug targets for future therapeutic interventions.
    [Show full text]
  • Twist2 Amplification in Rhabdomyosarcoma Represses Myogenesis and Promotes Oncogenesis by Redirecting Myod DNA Binding
    Downloaded from genesdev.cshlp.org on October 10, 2021 - Published by Cold Spring Harbor Laboratory Press Twist2 amplification in rhabdomyosarcoma represses myogenesis and promotes oncogenesis by redirecting MyoD DNA binding Stephen Li,1,2,3 Kenian Chen,4,5 Yichi Zhang,1,2,3 Spencer D. Barnes,6 Priscilla Jaichander,1,2,3 Yanbin Zheng,7,8 Mohammed Hassan,7,8 Venkat S. Malladi,6 Stephen X. Skapek,7,8 Lin Xu,2,4,5 Rhonda Bassel-Duby,1,2,3 Eric N. Olson,1,2,3 and Ning Liu1,2,3 1Department of Molecular Biology, 2Hamon Center for Regenerative Science and Medicine, 3Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, 4Quantitative Biomedical Research Center, 5Department of Clinical Sciences, 6Department of Bioinformatics, 7Department of Pediatrics, 8Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer composed of myoblast-like cells. Recently, we dis- covered a unique muscle progenitor marked by the expression of the Twist2 transcription factor. Genomic analyses of 258 RMS patient tumors uncovered prevalent copy number amplification events and increased expression of TWIST2 in fusion-negative RMS. Knockdown of TWIST2 in RMS cells results in up-regulation of MYOGENIN and a decrease in proliferation, implicating TWIST2 as an oncogene in RMS. Through an inducible Twist2 expression system, we identified Twist2 as a reversible inhibitor of myogenic differentiation with the remarkable ability to promote myotube dedifferentiation in vitro. Integrated analysis of genome-wide ChIP-seq and RNA-seq data re- vealed the first dynamic chromatin and transcriptional landscape of Twist2 binding during myogenic differentiation.
    [Show full text]
  • SATB Family Chromatin Organizers As Master Regulators of Tumor Progression
    Oncogene (2019) 38:1989–2004 https://doi.org/10.1038/s41388-018-0541-4 REVIEW ARTICLE SATB family chromatin organizers as master regulators of tumor progression 1 1 Rutika Naik ● Sanjeev Galande Received: 4 June 2018 / Revised: 30 August 2018 / Accepted: 2 September 2018 / Published online: 9 November 2018 © Springer Nature Limited 2018 Abstract SATB (Special AT-rich binding protein) family proteins have emerged as key regulators that integrate higher-order chromatin organization with the regulation of gene expression. Studies over the past decade have elucidated the specific roles of SATB1 and SATB2, two closely related members of this family, in cancer progression. SATB family chromatin organizers play diverse and important roles in regulating the dynamic equilibrium of apoptosis, cell invasion, metastasis, proliferation, angiogenesis, and immune modulation. This review highlights cellular and molecular events governed by SATB1 influencing the structural organization of chromatin and interacting with several co-activators and co-repressors of transcription towards tumor progression. SATB1 expression across tumor cell types generates cellular and molecular 1234567890();,: 1234567890();,: heterogeneity culminating in tumor relapse and metastasis. SATB1 exhibits dynamic expression within intratumoral cell types regulated by the tumor microenvironment, which culminates towards tumor progression. Recent studies suggested that cell-specific expression of SATB1 across tumor recruited dendritic cells (DC), cytotoxic T lymphocytes (CTL), T regulatory cells (Tregs) and tumor epithelial cells along with tumor microenvironment act as primary determinants of tumor progression and tumor inflammation. In contrast, SATB2 is differentially expressed in an array of cancer types and is involved in tumorigenesis. Survival analysis for patients across an array of cancer types correlated with expression of SATB family chromatin organizers suggested tissue-specific expression of SATB1 and SATB2 contributing to disease prognosis.
    [Show full text]
  • Regulation of the Foxp3 Gene by the Th1 Cytokines: the Role of IL-27-Induced STAT11
    The Journal of Immunology Regulation of the foxp3 Gene by the Th1 Cytokines: The Role of IL-27-Induced STAT11 Nadia Ouaked,* Pierre-Yves Mantel,*† Claudio Bassin,* Simone Burgler,* Kerstin Siegmund,* Cezmi A. Akdis,* and Carsten B. Schmidt-Weber2‡ Impaired functional activity of T regulatory cells has been reported in allergic patients and results in an increased suscep- tibility to autoimmune diseases. The master regulator of T regulatory cell differentiation, the transcription factor FOXP3, is required for both their development and function. Despite its key role, relatively little is known about the molecular mechanisms regulating foxp3 gene expression. In the present study, the effect of Th1 cytokines on human T regulatory cell differentiation was analyzed at epigenetic and gene expression levels and reveals a mechanism by which the STAT1-acti- vating cytokines IL-27 and IFN-␥ amplify TGF-␤-induced FOXP3 expression. This study shows STAT1 binding elements within the proximal part of the human FOXP3 promoter, which we previously hypothesized to function as a key regulatory unit. Direct binding of STAT1 to the FOXP3 promoter following IL-27 stimulation increases its transactivation process and induces permissive histone modifications in this key region of the FOXP3 promoter, suggesting that FOXP3 expression is promoted by IL-27 by two mechanisms. Our data demonstrate a molecular mechanism regulating FOXP3 expression, which is of considerable interest for the development of new drug targets aiming to support anti-inflammatory mechanisms of the immune system. The Journal of Immunology, 2009, 182: 1041–1049. ifferentiation of effector T cell subsets is an important tolerance against harmless non-self or self-Ags (6).
    [Show full text]