Interplay between cofactors and transcription factors in hematopoiesis and hematological malignancies

AbstractHematopoiesis requires finely tuned regulation of gene expression at each stage of development. The regulation of gene transcription involves not only individual transcription factors (TFs) but also transcription complexes (TCs) composed of transcription factor(s) and multisubunit cofactors. In their normal compositions, TCs orchestrate lineage-specific patterns of gene expression and ensure the production of the correct proportions of individual cell lineages during hematopoiesis. The integration of posttranslational and conformational modifications in the chromatin landscape, nucleosomes, histones and interacting components via the cofactor–TF interplay is critical to optimal TF activity. Mutations or translocations of cofactor genes are expected to alter cofactor–TF interactions, which may be causative for the pathogenesis of various hematologic disorders. Blocking TF oncogenic activity in hematologic disorders through targeting cofactors in aberrant complexes has been an exciting therapeutic strategy. In this review, we summarize the current knowledge regarding the models and functions of cofactor–TF interplay in physiological hematopoiesis and highlight their implications in the etiology of hematological malignancies. This review presents a deep insight into the physiological and pathological implications of transcription machinery in the blood system.

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Role of HDACs in normal and malignant hematopoiesis

Molecular Cancer ◽

10.1186/s12943-019-1127-7 ◽

2020 ◽

Vol 19 (1) ◽

Cited By ~ 14

Author(s):

Pan Wang ◽

Zi Wang ◽

Jing Liu

Keyword(s):

Gene Expression ◽

Drug Resistance ◽

Histone Deacetylases ◽

Hematological Malignancies ◽

Current Knowledge ◽

Hdac Inhibitors ◽

Vital Role ◽

Nonhistone Proteins ◽

Stage Of Development ◽

Differentiation And Proliferation

AbstractNormal hematopoiesis requires the accurate orchestration of lineage-specific patterns of gene expression at each stage of development, and epigenetic regulators play a vital role. Disordered epigenetic regulation has emerged as a key mechanism contributing to hematological malignancies. Histone deacetylases (HDACs) are a series of key transcriptional cofactors that regulate gene expression by deacetylation of lysine residues on histone and nonhistone proteins. In normal hematopoiesis, HDACs are widely involved in the development of various lineages. Their functions involve stemness maintenance, lineage commitment determination, cell differentiation and proliferation, etc. Deregulation of HDACs by abnormal expression or activity and oncogenic HDAC-containing transcriptional complexes are involved in hematological malignancies. Currently, HDAC family members are attractive targets for drug design, and a variety of HDAC-based combination strategies have been developed for the treatment of hematological malignancies. Drug resistance and limited therapeutic efficacy are key issues that hinder the clinical applications of HDAC inhibitors (HDACis). In this review, we summarize the current knowledge of how HDACs and HDAC-containing complexes function in normal hematopoiesis and highlight the etiology of HDACs in hematological malignancies. Moreover, the implication and drug resistance of HDACis are also discussed. This review presents an overview of the physiology and pathology of HDACs in the blood system.

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Regulation of gene expression by hypoxia

Biochemical Journal ◽

10.1042/bj20081055 ◽

2008 ◽

Vol 414 (1) ◽

pp. 19-29 ◽

Cited By ~ 159

Author(s):

Niall Steven Kenneth ◽

Sonia Rocha

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Cellular Response ◽

Current Knowledge ◽

Regulation Of Gene Expression ◽

Hypoxia Inducible Factor ◽

Translation Regulation ◽

Cellular Gene ◽

Cellular Pathways ◽

Molecular Aspects

Hypoxia induces profound changes in the cellular gene expression profile. The discovery of a major transcription factor family activated by hypoxia, HIF (hypoxia-inducible factor), and the factors that contribute to HIF regulation have greatly enhanced our knowledge of the molecular aspects of the hypoxic response. However, in addition to HIF, other transcription factors and cellular pathways are activated by exposure to reduced oxygen. In the present review, we summarize the current knowledge of how additional hypoxia-responsive transcription factors integrate with HIF and how other cellular pathways such as chromatin remodelling, translation regulation and microRNA induction, contribute to the co-ordinated cellular response observed following hypoxic stress.

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Runx transcription factors in the development and function of the definitive hematopoietic system

Blood ◽

10.1182/blood-2016-12-689109 ◽

2017 ◽

Vol 129 (15) ◽

pp. 2061-2069 ◽

Cited By ~ 44

Author(s):

Marella de Bruijn ◽

Elaine Dzierzak

Keyword(s):

Transcription Factors ◽

Current Knowledge ◽

Biological Effects ◽

Regulation Of Gene Expression ◽

Loss Of Function ◽

Specific Expression ◽

Hematopoietic Stem ◽

Hematopoietic Development ◽

Cell Lineages ◽

And Function

AbstractThe Runx family of transcription factors (Runx1, Runx2, and Runx3) are highly conserved and encode proteins involved in a variety of cell lineages, including blood and blood-related cell lineages, during developmental and adult stages of life. They perform activation and repressive functions in the regulation of gene expression. The requirement for Runx1 in the normal hematopoietic development and its dysregulation through chromosomal translocations and loss-of-function mutations as found in acute myeloid leukemias highlight the importance of this transcription factor in the healthy blood system. Whereas another review will focus on the role of Runx factors in leukemias, this review will provide an overview of the normal regulation and function of Runx factors in hematopoiesis and focus particularly on the biological effects of Runx1 in the generation of hematopoietic stem cells. We will present the current knowledge of the structure and regulatory features directing lineage-specific expression of Runx genes, the models of embryonic and adult hematopoietic development that provide information on their function, and some of the mechanisms by which they affect hematopoietic function.

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Automated generation of context-specific Gene Regulatory Networks with a weighted approach in D. melanogaster

10.1101/2020.08.03.232959 ◽

2020 ◽

Author(s):

Leandro Murgas ◽

Sebastian Contreras-Riquelme ◽

J. Eduardo Martínez ◽

Camilo Villaman ◽

Rodrigo Santibáñez ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Current Knowledge ◽

Regulation Of Gene Expression ◽

Chromatin Accessibility ◽

Reference Network ◽

Specific Gene ◽

Gene Regulatory

AbstractMotivationThe regulation of gene expression is a key factor in the development and maintenance of life in all organisms. This process is carried out mainly through the action of transcription factors (TFs), although other actors such as ncRNAs are involved. In this work, we propose a new method to construct Gene Regulatory Networks (GRNs) depicting regulatory events in a certain context for Drosophila melanogaster. Our approach is based on known relationships between epigenetics and the activity of transcription factors.ResultsWe developed method, Tool for Weighted Epigenomic Networks in D. melanogaster (Fly T-WEoN), which generates GRNs starting from a reference network that contains all known gene regulations in the fly. Regulations that are unlikely taking place are removed by applying a series of knowledge-based filters. Each of these filters is implemented as an independent module that considers a type of experimental evidence, including DNA methylation, chromatin accessibility, histone modifications, and gene expression. Fly T-WEoN is based on heuristic rules that reflect current knowledge on gene regulation in D. melanogaster obtained from literature. Experimental data files can be generated with several standard procedures and used solely when and if available.Fly T-WEoN is available as a Cytoscape application that permits integration with other tools, and facilitates downstream network analysis. In this work, we first demonstrate the reliability of our method to then provide a relevant application case of our tool: early development of D. melanogaster.AvailabilityFly T-WEoN, together with its step-by-step guide is available at https://[email protected]

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

Biochemistry and Cell Biology ◽

10.1139/o05-062 ◽

2005 ◽

Vol 83 (4) ◽

pp. 535-547 ◽

Cited By ~ 7

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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Transcription Factors as the “Blitzkrieg” of Plant Defense: A Pragmatic View of Nitric Oxide’s Role in Gene Regulation

International Journal of Molecular Sciences ◽

10.3390/ijms22020522 ◽

2021 ◽

Vol 22 (2) ◽

pp. 522

Author(s):

Noreen Falak ◽

Qari Muhammad Imran ◽

Adil Hussain ◽

Byung-Wook Yun

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Plant Defense ◽

Systemic Acquired Resistance ◽

Defense Mechanism ◽

Regulation Of Gene Expression ◽

Acquired Resistance ◽

Biological Processes ◽

Genetic Components ◽

Transcriptional Changes

Plants are in continuous conflict with the environmental constraints and their sessile nature demands a fine-tuned, well-designed defense mechanism that can cope with a multitude of biotic and abiotic assaults. Therefore, plants have developed innate immunity, R-gene-mediated resistance, and systemic acquired resistance to ensure their survival. Transcription factors (TFs) are among the most important genetic components for the regulation of gene expression and several other biological processes. They bind to specific sequences in the DNA called transcription factor binding sites (TFBSs) that are present in the regulatory regions of genes. Depending on the environmental conditions, TFs can either enhance or suppress transcriptional processes. In the last couple of decades, nitric oxide (NO) emerged as a crucial molecule for signaling and regulating biological processes. Here, we have overviewed the plant defense system, the role of TFs in mediating the defense response, and that how NO can manipulate transcriptional changes including direct post-translational modifications of TFs. We also propose that NO might regulate gene expression by regulating the recruitment of RNA polymerase during transcription.

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Minireview: Transcriptional Regulation in Development of Bone

Endocrinology ◽

10.1210/en.2004-1343 ◽

2005 ◽

Vol 146 (3) ◽

pp. 1012-1017 ◽

Cited By ~ 108

Author(s):

Tatsuya Kobayashi ◽

Henry Kronenberg

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Transcription Factors ◽

Bone Cells ◽

Genetic Manipulation ◽

Bone Development ◽

Regulation Of Gene Expression ◽

Bone Cell ◽

Cellular Functions ◽

Multiple Differentiation

Regulation of gene expression by transcription factors is one of the major mechanisms for controlling cellular functions. Recent advances in genetic manipulation of model animals has allowed the study of the roles of various genes and their products in physiological settings and has demonstrated the importance of specific transcription factors in bone development. Three lineages of bone cells, chondrocytes, osteoblasts, and osteoclasts, develop and differentiate according to their distinct developmental programs. These cells go through multiple differentiation stages, which are often regulated by specific transcription factors. In this minireview, we will discuss selected transcription factors that have been demonstrated to critically affect bone cell development. Further study of these molecules will lead to deeper understanding in mechanisms that govern development of bone.

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How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease

Cells ◽

10.3390/cells10102611 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2611

Author(s):

Jayron J. Habibe ◽

Maria P. Clemente-Olivo ◽

Carlie J. de Vries

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Current Knowledge ◽

Genetic Regulation ◽

Regulation Of Gene Expression ◽

Lim Domain ◽

Multifactorial Diseases ◽

Lim Domains ◽

Age Related

Susceptibility to complex pathological conditions such as obesity, type 2 diabetes and cardiovascular disease is highly variable among individuals and arises from specific changes in gene expression in combination with external factors. The regulation of gene expression is determined by genetic variation (SNPs) and epigenetic marks that are influenced by environmental factors. Aging is a major risk factor for many multifactorial diseases and is increasingly associated with changes in DNA methylation, leading to differences in gene expression. Four and a half LIM domains 2 (FHL2) is a key regulator of intracellular signal transduction pathways and the FHL2 gene is consistently found as one of the top hyper-methylated genes upon aging. Remarkably, FHL2 expression increases with methylation. This was demonstrated in relevant metabolic tissues: white adipose tissue, pancreatic β-cells, and skeletal muscle. In this review, we provide an overview of the current knowledge on regulation of FHL2 by genetic variation and epigenetic DNA modification, and the potential consequences for age-related complex multifactorial diseases.

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