Epigenetic control of hematopoiesis: the PU.1 chromatin connection

2014 ◽  
Vol 395 (11) ◽  
pp. 1265-1274 ◽  
Author(s):  
Boet van Riel ◽  
Frank Rosenbauer
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Current Knowledge ◽  
Dna Methyltransferases ◽  
Chromatin Remodelers ◽  
Cell Lineages ◽  
Protein Partners ◽  
Genome Wide

Abstract Purine-rich box1 (PU.1) is a transcription factor that not only has a key role in the development of most hematopoietic cell lineages but also in the suppression of leukemia. To exert these functions, PU.1 can cross-talk with multiple different proteins by forming complexes in order to activate or repress transcription. Among its protein partners are chromatin remodelers, DNA methyltransferases, and a number of other transcription factors with important roles in hematopoiesis. While a great deal of knowledge has been acquired about PU.1 function over the years, it was the development of novel genome-wide technologies, which boosted our understanding of how PU.1 acts on the chromatin to drive its repertoire of target genes. This review summarizes current knowledge and ideas of molecular mechanisms by which PU.1 controls hematopoiesis and suppresses leukemia.

scholarly journals Genome-wide reduction in chromatin accessibility and unique transcription factor footprints in endothelial cells and fibroblasts in scleroderma skin

2020 ◽  
Author(s):  
Pei-Suen Tsou ◽  
Pamela J. Palisoc ◽  
Mustafa Ali ◽  
Dinesh Khanna ◽  
Amr H Sawalha
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Target Genes ◽  
Critical Role ◽  
Vascular Complications ◽  
Chromatin Accessibility ◽  
Unknown Etiology ◽  
Healthy Controls ◽  
Genome Wide

AbstractSystemic sclerosis (SSc) is a rare autoimmune disease of unknown etiology characterized by widespread fibrosis and vascular complications. We utilized an assay for genome-wide chromatin accessibility to examine the chromatin landscape and transcription factor footprints in both endothelial cells (ECs) and fibroblasts isolated from healthy controls and patients with diffuse cutaneous (dc) SSc. In both cell types, chromatin accessibility was significantly reduced in SSc patients compared to healthy controls. Genes annotated from differentially accessible chromatin regions were enriched in pathways and gene ontologies involved in the nervous system. In addition, our data revealed that chromatin binding of transcription factors SNAI2, ETV2, and ELF1 was significantly increased in dcSSc ECs, while recruitment of RUNX1 and RUNX2 was enriched in dcSSc fibroblasts. Significant elevation of SNAI2 and ETV2 levels in dcSSc ECs, and RUNX2 levels in dcSSc fibroblasts were confirmed. Further analysis of publicly available ETV2-target genes suggests that ETV2 may play a critical role in EC dysfunction in dcSSc. Our data, for the first time, uncovered the chromatin blueprint of dcSSc ECs and fibroblasts, and suggested that neural-related characteristics of SSc ECs and fibroblasts could be a culprit for dysregulated angiogenesis and enhanced fibrosis. Targeting these pathways and the key transcription factors identified might present novel therapeutic approaches for this disease.

Hox transcription factors: an overview of multi-step regulators of gene expression

2018 ◽  
Vol 62 (11-12) ◽  
pp. 723-732 ◽  
Author(s):  
Julie Carnesecchi ◽  
Pedro B. Pinto ◽  
Ingrid Lohmann
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cell Fates ◽  
Hox Proteins ◽  
Regulatory Modules ◽  
Genome Wide ◽  
Transcription Complexes ◽  
Regulatory Functions

Hox transcription factors (TFs) function as key determinants in the specification of cell fates during development. They do so by triggering entire morphogenetic cascades through the activation of specific target genes. In contrast to their fundamental role in development, the molecular mechanisms employed by Hox TFs are still poorly understood. In recent years, a new picture has emerged regarding the function of Hox proteins in gene regulation. Initial studies have primarily focused on understanding how Hox TFs recognize and bind specific enhancers to activate defined Hox targets. However, genome-wide studies on the interactions and dynamics of Hox proteins have revealed a more elaborate function of the Hox factors. It is now known that Hox proteins are involved in several steps of gene expression with potential regulatory functions in the modification of the chromatin landscape and its accessibility, recognition and activation of specific cis-regulatory modules, assembly and activation of promoter transcription complexes and mRNA processing. In the coming years, the characterization of the molecular activity of Hox TFs in these mechanisms will greatly contribute to our general understanding of Hox activity.

Activation Functions 1 and 2 of Nuclear Receptors: Molecular Strategies for Transcriptional Activation

2003 ◽  
Vol 17 (10) ◽  
pp. 1901-1909 ◽  
Author(s):  
Anette Wärnmark ◽  
Eckardt Treuter ◽  
Anthony P. H. Wright ◽  
Jan-Åke Gustafsson
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Current Knowledge ◽  
Preinitiation Complex ◽  
Activation Domains ◽  
Terminal Domain

Abstract Nuclear receptors (NRs) comprise a family of ligand inducible transcription factors. To achieve transcriptional activation of target genes, DNA-bound NRs directly recruit general transcription factors (GTFs) to the preinitiation complex or bind intermediary factors, so-called coactivators. These coactivators often constitute subunits of larger multiprotein complexes that act at several functional levels, such as chromatin remodeling, enzymatic modification of histone tails, or modulation of the preinitiation complex via interactions with RNA polymerase II and GTFs. The binding of NR to coactivators is often mediated through one of its activation domains. Many NRs have at least two activation domains, the ligand-independent activation function (AF)-1, which resides in the N-terminal domain, and the ligand-dependent AF-2, which is localized in the C-terminal domain. In this review, we summarize and discuss current knowledge regarding the molecular mechanisms of AF-1- and AF-2-mediated gene activation, focusing on AF-1 and AF-2 conformation and coactivator binding.

scholarly journals DNMTs and Impact of CpG Content, Transcription Factors, Consensus Motifs, lncRNAs, and Histone Marks on DNA Methylation

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1336 ◽  
Author(s):  
Jaqueline Loaeza-Loaeza ◽  
Adriana S. Beltran ◽  
Daniel Hernández-Sotelo
Keyword(s):  
Dna Methylation ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Current Knowledge ◽  
Dna Methyltransferases ◽  
Histone Marks ◽  
Spatiotemporal Regulation ◽  
Genome Wide ◽  
Health And Disease ◽  
Methylation Patterns

DNA methyltransferases (DNMTs) play an essential role in DNA methylation and transcriptional regulation in the genome. DNMTs, along with other poorly studied elements, modulate the dynamic DNA methylation patterns of embryonic and adult cells. We summarize the current knowledge on the molecular mechanism of DNMTs’ functional targeting to maintain genome-wide DNA methylation patterns. We focus on DNMTs’ intrinsic characteristics, transcriptional regulation, and post-transcriptional modifications. Furthermore, we focus special attention on the DNMTs’ specificity for target sites, including key cis-regulatory factors such as CpG content, common motifs, transcription factors (TF) binding sites, lncRNAs, and histone marks to regulate DNA methylation. We also review how complexes of DNMTs/TFs or DNMTs/lncRNAs are involved in DNA methylation in specific genome regions. Understanding these processes is essential because the spatiotemporal regulation of DNA methylation modulates gene expression in health and disease.

scholarly journals The Scleraxis Transcription Factor Directly Regulates Multiple Distinct Molecular and Cellular Processes During Early Tendon Cell Differentiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Han Liu ◽  
Jingyue Xu ◽  
Yu Lan ◽  
Hee-Woong Lim ◽  
Rulang Jiang
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Seq ◽  
Tendon Cell ◽  
Tendon Development ◽  
Genome Wide ◽  
Direct Target ◽  
Embryonic Tendon

Proper development of tendons is crucial for the integration and function of the musculoskeletal system. Currently little is known about the molecular mechanisms controlling tendon development and tendon cell differentiation. The transcription factor Scleraxis (Scx) is expressed throughout tendon development and plays essential roles in both embryonic tendon development and adult tendon healing, but few direct target genes of Scx in tendon development have been reported and genome-wide identification of Scx direct target genes in vivo has been lacking. In this study, we have generated a ScxFlag knockin mouse strain, which produces fully functional endogenous Scx proteins containing a 2xFLAG epitope tag at the carboxy terminus. We mapped the genome-wide Scx binding sites in the developing limb tendon tissues, identifying 12,097 high quality Scx regulatory cis-elements in-around 7,520 genes. Comparative analysis with previously reported embryonic tendon cell RNA-seq data identified 490 candidate Scx direct target genes in early tendon development. Furthermore, we characterized a new Scx gene-knockout mouse line and performed whole transcriptome RNA sequencing analysis of E15.5 forelimb tendon cells from Scx–/– embryos and control littermates, identifying 68 genes whose expression in the developing tendon tissues significantly depended on Scx function. Combined analysis of the ChIP-seq and RNA-seq data yielded 32 direct target genes that required Scx for activation and an additional 17 target genes whose expression was suppressed by Scx during early tendon development. We further analyzed and validated Scx-dependent tendon-specific expression patterns of a subset of the target genes, including Fmod, Kera, Htra3, Ssc5d, Tnmd, and Zfp185, by in situ hybridization and real-time quantitative polymerase chain reaction assays. These results provide novel insights into the molecular mechanisms mediating Scx function in tendon development and homeostasis. The ChIP-seq and RNA-seq data provide a rich resource for aiding design of further studies of the mechanisms regulating tendon cell differentiation and tendon tissue regeneration. The ScxFlag mice provide a valuable new tool for unraveling the molecular mechanisms involving Scx in the protein interaction and gene-regulatory networks underlying many developmental and disease processes.

scholarly journals Research Resource: Genome-Wide Profiling of Progesterone Receptor Binding in the Mouse Uterus

2012 ◽  
Vol 26 (8) ◽  
pp. 1428-1442 ◽  
Author(s):  
Cory A. Rubel ◽  
Rainer B. Lanz ◽  
Ramakrishna Kommagani ◽  
Heather L. Franco ◽  
John P. Lydon ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Progesterone Receptor ◽  
Binding Sites ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Massively Parallel Sequencing ◽  
Mouse Uterus ◽  
Ovariectomized Mice ◽  
Genome Wide ◽  
Uterine Function

Progesterone (P4) signaling through its nuclear transcription factor, the progesterone receptor (PR), is essential for normal uterine function. Although deregulation of PR-mediated signaling is known to underscore uterine dysfunction and a number of endometrial pathologies, the early molecular mechanisms of this deregulation are unclear. To address this issue, we have defined the genome-wide PR cistrome in the murine uterus using chromatin immunoprecipitation (ChIP) followed by massively parallel sequencing (ChIP-seq). In uteri of ovariectomized mice, we identified 6367 PR-binding sites in the absence of P4 ligand; however, this number increased at nearly 3-fold (18,432) after acute P4 exposure. Sequence analysis revealed that approximately 73% of these binding sites contain a progesterone response element or a half-site motif recognized by the PR. Many previously identified P4 target genes known to regulate uterine function were found to contain PR-binding sites, confirming the validity of our methodology. Interestingly, when the ChIP-seq data were coupled with our microarray expression data, we identified a novel regulatory role for uterine P4 in circadian rhythm gene expression, thereby uncovering a hitherto unexpected new circadian biology for P4 in this tissue. Further mining of the ChIP-seq data revealed Sox17 as a direct transcriptional PR target gene in the uterus. As a member of the Sox transcription factor family, Sox17 represents a potentially novel mediator of PR action in the murine uterus. Collectively, our first line of analysis of the uterine PR cistrome provides the first insights into the early molecular mechanisms that underpin normal uterine responsiveness to acute P4 exposure. Future analysis promises to reveal the PR interactome and, in turn, potential therapeutic targets for the diagnosis and/or treatment of endometrial dysfunction.

scholarly journals Review of the in Vivo Functions of the p160 Steroid Receptor Coactivator Family

2003 ◽  
Vol 17 (9) ◽  
pp. 1681-1692 ◽  
Author(s):  
Jianming Xu ◽  
Qingtian Li
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Steroid Receptor ◽  
Molecular Structures ◽  
Endocrine Regulation ◽  
Steroid Receptor Coactivator

Abstract The p160 steroid receptor coactivator (SRC) gene family contains three homologous members, which serve as transcriptional coactivators for nuclear receptors and certain other transcription factors. These coactivators interact with ligand-bound nuclear receptors to recruit histone acetyltransferases and methyltransferases to specific enhancer/promotor regions, which facilitates chromatin remodeling, assembly of general transcription factors, and transcription of target genes. This minireview summarizes our current knowledge about the molecular structures, molecular mechanisms, temporal and spatial expression patterns, and biological functions of the SRC family. In particular, this article highlights the roles of SRC-1 (NCoA-1), SRC-2 (GRIP1, TIF2, or NCoA-2) and SRC-3 (p/CIP, RAC3, ACTR, AIB1, or TRAM-1) in development, organ function, endocrine regulation, and nuclear receptor function, which are defined by characterization of the genetically manipulated animal models. Furthermore, this article also reviews our current understanding of the role of SRC-3 in breast cancer and discusses possible mechanisms for functional specificity and redundancy among SRC family members.

scholarly journals Genome-wide strategies reveal target genes of Npas4l associated with cardiovascular development in zebrafish

2018 ◽  
Author(s):  
Michele Marass ◽  
Arica Beisaw ◽  
Claudia Gerri ◽  
Francesca Luzzani ◽  
Nana Fukuda ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chromatin Immunoprecipitation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Building Blocks ◽  
Phenotypic Characterization ◽  
Cardiovascular Development ◽  
Genome Wide ◽  
Transcription Factor Genes

ABSTRACTThe development of a vascular network is essential to nourish tissues and sustain organ function throughout life. Endothelial cells (ECs) are the building blocks of blood vessels, yet our understanding of EC specification remains incomplete. zebrafish cloche/npas4l mutants have been used broadly as an avascular model, but little is known about the molecular mechanisms of action of the Npas4l transcription factor. Here, to identify its direct and indirect target genes, we combined complementary genome-wide approaches including transcriptome analyses and chromatin immunoprecipitation (ChIP). The cross-analysis of these datasets indicates that Npas4l functions as a master regulator by directly inducing a group of transcription factor genes crucial for hematoendothelial specification such as etv2, tal1 and lmo2. We also identified new targets of Npas4l and investigated the function of a subset of them using the CRISPR/Cas9 technology. Phenotypic characterization of tspan18b mutants reveals a novel player in developmental angiogenesis, confirming the reliability of the datasets generated. Collectively, these data represent a useful resource for future studies aimed to better understand EC fate determination and vascular development.

scholarly journals GABP controls a critical transcription regulatory module that is essential for maintenance and differentiation of hematopoietic stem/progenitor cells

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2166-2178 ◽  
Author(s):  
Shuyang Yu ◽  
Kairong Cui ◽  
Raja Jothi ◽  
Dong-Mei Zhao ◽  
Xuefang Jing ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Progenitor Cells ◽  
Target Genes ◽  
Dna Methyltransferases ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Genome Wide ◽  
Regulatory Module ◽  
Absolute Dependence ◽  
Multiple Blood

Abstract Maintaining a steady pool of self-renewing hematopoietic stem cells (HSCs) is critical for sustained production of multiple blood lineages. Many transcription factors and molecules involved in chromatin and epigenetic modifications have been found to be critical for HSC self-renewal and differentiation; however, their interplay is less understood. The transcription factor GA binding protein (GABP), consisting of DNA-binding subunit GABPα and transactivating subunit GABPβ, is essential for lymphopoiesis as shown in our previous studies. Here we demonstrate cell-intrinsic, absolute dependence on GABPα for maintenance and differentiation of hematopoietic stem/progenitor cells. Through genome-wide mapping of GABPα binding and transcriptomic analysis of GABPα-deficient HSCs, we identified Zfx and Etv6 transcription factors and prosurvival Bcl-2 family members including Bcl-2, Bcl-XL, and Mcl-1 as direct GABP target genes, underlying its pivotal role in HSC survival. GABP also directly regulates Foxo3 and Pten and hence sustains HSC quiescence. Furthermore, GABP activates transcription of DNA methyltransferases and histone acetylases including p300, contributing to regulation of HSC self-renewal and differentiation. These systematic analyses revealed a GABP-controlled gene regulatory module that programs multiple aspects of HSC biology. Our studies thus constitute a critical first step in decoding how transcription factors are orchestrated to regulate maintenance and multipotency of HSCs.

Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression

2005 ◽  
Vol 83 (4) ◽  
pp. 535-547 ◽  
Author(s):  
Gareth N Corry ◽  
D Alan Underhill
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Current Knowledge ◽  
Nuclear Architecture ◽  
Subnuclear Localization ◽  
Modular Structures

To date, the majority of the research regarding eukaryotic transcription factors has focused on characterizing their function primarily through in vitro methods. These studies have revealed that transcription factors are essentially modular structures, containing separate regions that participate in such activities as DNA binding, protein–protein interaction, and transcriptional activation or repression. To fully comprehend the behavior of a given transcription factor, however, these domains must be analyzed in the context of the entire protein, and in certain cases the context of a multiprotein complex. Furthermore, it must be appreciated that transcription factors function in the nucleus, where they must contend with a variety of factors, including the nuclear architecture, chromatin domains, chromosome territories, and cell-cycle-associated processes. Recent examinations of transcription factors in the nucleus have clarified the behavior of these proteins in vivo and have increased our understanding of how gene expression is regulated in eukaryotes. Here, we review the current knowledge regarding sequence-specific transcription factor compartmentalization within the nucleus and discuss its impact on the regulation of such processes as activation or repression of gene expression and interaction with coregulatory factors.Key words: transcription, subnuclear localization, chromatin, gene expression, nuclear architecture.

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