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Results for “Targeting chromatin regulators”

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PubMed2019

Profiling the long noncoding RNA interaction network in the regulatory elements of target genes by chromatin in situ reverse transcription sequencing.

Long noncoding RNAs (lncRNAs) can regulate the activity of target genes by participating in the organization of chromatin architecture. We have devised a "chromatin-RNA in situ reverse transcription sequencing" (CRIST-seq) approach to profile the lncRNA interaction network in gene regulatory elements by combining the simplicity of RNA biotin labeling with the specificity of the CRISPR/Cas9 system. Using gene-specific gRNAs, we describe a pluripotency-specific lncRNA interacting network in the promoters of Sox2 and Pou5f1, two critical stem cell factors that are required for the maintenance of pluripotency. The promoter-interacting lncRNAs were specifically activated during reprogramming into pluripotency. Knockdown of these lncRNAs caused the stem cells to exit from pluripotency. In contrast, overexpression of the pluripotency-associated lncRNA activated the promoters of core stem cell factor genes and enhanced fibroblast reprogramming into pluripotency. These CRIST-seq data suggest that the Sox2 and Pou5f1 promoters are organized within a unique lncRNA interaction network that determines the fate of pluripotency during reprogramming. This CRIST approach may be broadly used to map lncRNA interaction networks at target loci across the genome.

Animals↗

PubMed2003

Collaborative spirit of histone deacetylases in regulating chromatin structure and gene expression.

The flexible N-terminal tails of core histones are subject to dynamic, reversible lysine acetylation. At least 10 histone deacetylases have been identified in Saccharomyces cerevisiae and 19 in humans. Emerging themes regarding the function and regulation of these enzymes include the following: targeted and non-targeted chromatin deacetylation; their collaboration with each other and with other chromatin regulators to promote transcriptional repression and silencing; deacetylation of transcription factors and other non-histone proteins; and regulation by subcellular compartmentalization and subunit association. Histone deacetylases are important targets for drugs with potential therapeutic value in the treatment of cancer, neurodegenerative disorders, cardiac hypertrophy and other human diseases.

Chromatin↗

PubMed2026

Target-Site Selection by Transcription Factors: Roles of DNA, Chromatin, and Cofactor-Mediated Regulation.

Transcription factors (TFs) are sequence-specific DNA-binding proteins that regulate gene-expression programs and cell fate. The ability of a defined combination of four TFs to reprogram differentiated cells into induced pluripotent stem cells illustrates the powerful role of TFs in determining cellular identity. However, TFs usually recognize short and degenerate DNA motifs of approximately 6-12 base pairs, generating thousands to millions of potential motif matches in mammalian genomes. In living cells, TFs occupy only a restricted subset of these sites, indicating that motif presence alone is insufficient for functional target selection. Several layers of regulation contribute to this selective occupancy, including DNA methylation, nucleosome organization, histone modifications, chromatin remodeling, TF oligomerization, TF availability and localization, and cofactors that regulate DNA-binding domains. This review outlines how DNA/chromatin features and TF-centered mechanisms contribute to target-site selection. The principal aim is to highlight DNA-binding domain-directed cofactor regulation as an underappreciated mechanism that modulates TF-DNA binding and may help explain selective genomic occupancy.

Target-site selection↗

PubMed2002

A feel for the template: zinc finger protein transcription factors and chromatin.

Transcription factors and chromatin collaborate in bringing the eukaryotic genome to life. An important, and poorly understood, aspect of this collaboration involves targeting the regulators to correct binding sites in vivo. An implicit and insufficiently tested assumption in the field has been that chromatin simply obstructs most sites and leaves only a few functionally relevant ones accessible. The major class of transcription factors in all metazoa, zinc finger proteins (ZFPs), can bind to chromatin in vitro (as clearly shown for Spl, GATA-1 and -4, and the nuclear hormone receptors, for example). Data on the accessibility of DNA within heterochromatin to nonhistone regulators (E.A. Sekinger and D.S. Gross. 2001. Mol. Cell 105: 403-414; C. Jolly et al. 2002. J. Cell. Biol. 156: 775-781) and the ability of the basal transcription machinery to reside within highly condensed chromatin (most recently, R. Christova and T. Oelgeschlaeger. 2002. Nat. Cell Biol. 4: 79-82) further weaken the argument that chromatin acts as an across-the-board deterrent to ZFP binding. These proteins, however, do not bind promiscuously in vivo, and recent data on human cells (C.E. Horak et al. 2002. Proc. Natl. Acad. Sci. U.S.A. 99: 2924-2929) confirm earlier data on budding yeast (B. Ren et al. 2000. Science (Washington, D.C.), 290: 2306-2309) that primary DNA sequence, i.e., density of binding sites per unit DNA length, is not the primary determinant of where a ZFP transcription factor will bind in vivo. This article reviews these data and uses ZFP transcription factors as a model system to compare in vitro binding to chromatin by transcription factors with their in vivo behavior in gene regulation. DNA binding domain structure, nonrandom nucleoprotein organization of chromatin at target promoters, and cooperativity of regulator action may all contribute to target site selection in vivo.

Binding Sites↗

PubMed1994

Characterisation of T48, a target of homeotic gene regulation in Drosophila embryogenesis.

In Drosophila, the homeotic genes encode transcription factors which specify segmental identities during embryogenesis by directly regulating subordinate target genes. A chromatin immunopurification approach has been used to identify targets of the homeotic gene Ultrabithorax (Ubx). We report here the characterisation of a candidate target gene which is positively regulated by the homeotic genes Ubx and abdominal-A in both the epidermis and the midgut visceral mesoderm and encodes a novel transmembrane protein. By mapping the cis-regulatory regions of this gene, we have identified elements responsible for mediating homeotic regulation, and show that they contain in vitro Ubx binding sites. Therefore, we suggest that this is an example of a direct target of regulation by homeotic genes in two germlayers.

Amino Acid Sequence↗

PubMed2001

Emerging roles for chromatin remodeling in cancer biology.

Cell proliferation and differentiation are guided by changes in gene expression and require the coordinated efforts of the transcription machinery and chromatin-remodeling factors. However, aberrant regulation of chromatin structure can arise through mutations in chromatin-modifying and -remodeling proteins and can lead to improper gene expression and cancer. This review discusses how mutations in chromatin regulators might affect their targeting or activity, with an emphasis on the important insights revealed by leukemogenic fusion proteins. Understanding the normal and oncogenic role of these factors will be crucial for the design of therapeutic agents.

Acetyltransferases↗

PubMed2025

A targeted CRISPR screen identifies ETS1 as a regulator of HIV-1 latency.

Human Immunodeficiency virus (HIV) infection is regulated by a wide array of host cell factors that combine to influence viral transcription and latency. To understand the complex relationship between the host cell and HIV-1 latency, we performed a lentiviral CRISPR screen that targeted a set of host cell genes whose expression or activity correlates with HIV-1 expression. We further investigated one of the identified factors - the transcription factor ETS1, and found that it is required for maintenance of HIV-1 latency in both latently infected cell lines and in a primary CD4 T cell latency model. Interestingly, ETS1 played divergent roles in actively infected and latently infected CD4 T cells, with knockout of ETS1 leading to reduced HIV-1 expression in actively infected cells, but increased HIV-1 expression in latently infected cells, indicating that ETS1 can play both a positive and negative role in HIV-1 expression. CRISPR/Cas9 knockout of ETS1 in CD4 T cells from ART-suppressed people with HIV-1 (PWH) confirmed that ETS1 maintains transcriptional repression of the clinical HIV-1 reservoir. Transcriptomic profiling of ETS1-depleted cells from PWH identified a set of host cell pathways involved in viral transcription that are controlled by ETS1 in resting CD4 T cells. In particular, we observed that ETS1 knockout increased expression of the long non-coding RNA MALAT1 that has been previously identified as a positive regulator of HIV-1 expression. Furthermore, the impact of ETS1 depletion on HIV-1 expression in latently infected cells was partially dependent on MALAT1. Additionally, we demonstrate that ETS1 knockout resulted in enhanced abundance of activating modifications (H3K9Ac, H3K27Ac, H3K4me3) on histones located at the HIV-1 long terminal repeat (LTR), indicating that ETS1 regulates the activity of chromatin-targeting complexes at the HIV-1 LTR. Overall, these data demonstrate that ETS1 is an important regulator of HIV-1 latency that impacts HIV-1 expression through repressing MALAT1 expression and by regulating modification of proviral histones.

Proto-Oncogene Protein c-ets-1↗

PubMedDate not supplied

Signaling to the chromatin during skeletal myogenesis: novel targets for pharmacological modulation of gene expression.

Cellular differentiation entails an extensive reprogramming of the genome toward the expression of discrete subsets of genes, which establish the tissue-specific phenotype. This program is achieved by epigenetic marks of the chromatin at particular loci, and is regulated by environmental cues, such as soluble factors and cell-to-cell interactions. How the intracellular cascades convert the myriad of external stimuli into the nuclear information necessary to reprogram the genome toward specific responses is a question of biological and medical interest. The elucidation of the signaling converting cues from outside the cells into chromatin modifications at individual promoters holds the promise to unveil the targets for selective pharmacological interventions to modulate gene expression for therapeutic purposes. Enhancing muscle regeneration and preventing muscle breakdown are important goals in the therapy of muscular diseases, cancer-associated cachexia and aging-associated sarcopenia. We will summarize the recent progress of our knowledge of the regulation of gene expression by intracellular cascades elicited by external cues during skeletal myogenesis. And will illustrate the potential importance of targeting the chromatin signaling in regenerative medicine--e.g. to boost muscle regeneration.

Animals↗

PubMed1995

Genetic interactions and dosage effects of Polycomb group genes of Drosophila.

The Polycomb (Pc) group of genes are required for maintenance of cell determination in Drosophila melanogaster. At least 11 Pc group genes have been described and there may be up to 40; all are required for normal regulation of homeotic genes, but as a group, their phenotypes are rather diverse. It has been suggested that the products of Pc group genes might be members of a heteromeric complex that acts to regulate the chromatin structure of target loci. We examined the phenotypes of adult flies heterozygous for every pairwise combination of Pc group genes in an attempt to subdivide the Pc group functionally. The results support the idea that Additional sex combs (Asx), Pc, Polycomblike (Pcl), Posterior sex combs (Psc), Sex combs on midleg (Scm), and Sex combs extra (Sce) have similar functions in some imaginal tissues. We show genetic interactions among extra sex combs (esc) and Asx, Enhancer of Pc, Pcl, Enhancer of zeste E(z), and super sex combs and reassess the idea that most Pc group genes function independently of esc. Most duplications of Pc group genes neither exhibit anterior transformations nor suppress the extra sex comb phenotype of Pc group mutations, suggesting that not all Pc group genes behave as predicted by the mass-action model. Surprisingly, duplications of E(z) enhance homeotic phenotypes of esc mutants. Flies with increasing doses of esc+ exhibit anterior transformations, but these are not enhanced by mutations in trithorax group genes. The results are discussed with respect to current models of Pc group function.

Alleles↗

PubMed2006

Chromatin remodeling complex interacts with ADD1/SREBP1c to mediate insulin-dependent regulation of gene expression.

Insulin plays a critical role in whole-body energy homeostasis by regulating lipid and glucose metabolism. In fat and liver tissues, ADD1/SREBP1c is a key transcription factor to mediate insulin-dependent regulation of gene expression. Although transcriptional and proteolytic activation of ADD1/SREBP1c has been studied intensively, the mechanism by which insulin regulates expression of its target genes with ADD1/SREBP1c at the chromatin level is unclear. Here, we reveal that SWI/SNF chromatin remodeling factors interact with the ADD1/SREBP1c and actively regulate insulin-dependent gene expression. Insulin enhanced recruitment of SWI/SNF chromatin remodeling factors to its target gene promoters with concomitant changes in the chromatin structures as well as gene expression. Furthermore, in vivo overexpression of BAF155/SRG3, a component of the SWI/SNF complex, substantially promoted insulin target gene expression and insulin sensitivity. Taken together, our results suggest that the SWI/SNF chromatin remodeling complexes confer not only insulin-dependent gene expression but also insulin sensitivity in vivo via interaction with ADD1/SREBP1c.

3T3-L1 Cells↗

PubMed1991

Dopaminergic and ligand-independent activation of steroid hormone receptors.

The current view of how steroid hormone receptors affect gene transcription is that these receptors, on binding ligand, change to a state in which they can interact with chromatin and regulate transcription of target genes. Receptor activation is believed to be dependent only on this ligand-binding event. Selected steroid hormone receptors can be activated in a ligand-independent manner by a membrane receptor agonist, the neurotransmitter dopamine. In vitro, dopamine faithfully mimicked the effect of progesterone by causing a translocation of chicken progesterone receptor (cPR) from cytoplasm to nucleus. Dual activation by progesterone and dopamine was dissociable, and a serine residue in the cPR was identified that is not necessary for progesterone-dependent activation of cPR, but is essential for dopamine activation of this receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2004

Systematic identification and analysis of mammalian small ubiquitin-like modifier substrates.

Small ubiquitin-like modifier (SUMO) regulates diverse cellular processes through its reversible, covalent attachment to target proteins. Many SUMO substrates are involved in transcription and chromatin structure. Sumoylation appears to regulate the functions of target proteins by changing their subcellular localization, increasing their stability, and/or mediating their binding to other proteins. Using an in vitro expression cloning approach, we have identified 40 human SUMO1 substrates. The spectrum of human SUMO1 substrates identified in our screen suggests general roles of sumoylation in transcription, chromosome structure, and RNA processing. We have validated the sumoylation of 24 substrates in living cells. Analysis of this panel of SUMO substrates leads to the following observations. 1) Sumoylation is more efficient in vitro than in living cells. Polysumoylation occurs on several substrates in vitro. 2) SUMO isopeptidases have little substrate specificity. 3) The SUMO ligases, PIAS1 and PIASxbeta, have broader substrate specificities than does PIASy. 4) Although SUMO1 and SUMO2 are equally efficiently conjugated to a given substrate in vitro, SUMO1 conjugation is more efficient in vivo. 5) Most SUMO substrates localize to the nucleus, and sumoylation does not generally affect their subcellular localization. Therefore, sumoylation appears to regulate the functions of its substrates through multiple, context-dependent mechanisms.

DNA↗

PubMed2000

Targeted recruitment of histone acetyltransferase activity to a locus control region.

Locus control regions (LCRs) are capable of activating target genes over substantial distances and establishing autonomously regulated chromatin domains. The basis for this action is poorly defined. Human growth hormone gene (hGH-N) expression is activated by an LCR marked by a series of DNase I-hypersensitive sites (HSI-III and HSV) in pituitary chromatin. These HSs are located between -15 and -32 kilobases (kb) relative to the hGH transcription start site. To establish a mechanistic basis for hGH LCR function, we carried out acetylation mapping of core histones H3 and H4 in chromatin encompassing the hGH cluster. These studies revealed that the entire LCR was selectively enriched for acetylation in chromatin isolated from a human pituitary somatotrope adenoma and in pituitaries of mice transgenic for the hGH locus, but not in hepatic or erythroid cells. Quantification of histone modification in the pituitary revealed a dramatic peak at HSI/II, the major pituitary-specific hGH LCR determinant (-15 kb), with gradually decreasing levels of modification extending from this site in both 5'- and 3'-directions. The 5'-border of the acetylated domain coincided with the 5' most hGH LCR element, HSV (-34 kb); and the 3'-border included the expressed hGH-N gene, but did not extend farther 3' into the placenta-specific region of the gene cluster. These data support a model of LCR function involving targeted recruitment and subsequent spreading of histone acetyltransferase activity to encompass and activate a remote target gene.

Acetyltransferases↗

PubMed2026

Chromatin Remodeling Subunit ARID1A Negatively Regulates the Malignant Progression of Gastrointestinal Stromal Tumors by Targeting the MEMO1 Promoter.

Gastrointestinal stromal tumors (GISTs) are the most common sarcomas of the alimentary tract and are primarily characterized by malignant progression, a major cause of mortality. AT-rich interaction domain 1A (ARID1A), a core component of the chromatin-remodeling SWI/SNF complex, has been found to correlate with GIST tumor grade, although the underlying mechanism remains unclear. Its frequent inactivation across diverse cancer types reveals pleiotropic roles that intersect multiple hallmarks of cancer. In this study, we aimed to investigate the potential relationship between ARID1A and malignant progression in GISTs, as well as the underlying mechanism. Western blotting, real-time polymerase chain reaction, and immunohistochemistry were used to assess ARID1A expression in GIST tissues. Cell Counting Kit-8 (CCK-8) assays were performed to evaluate cell proliferation. Wound-healing and Transwell assays were conducted to assess cell migration and invasion. Flow cytometry was used to analyze apoptosis and cell cycle distribution. Label-free quantitative proteomics and chromatin immunoprecipitation sequencing (ChIP-seq) were employed to identify top candidate downstream targets of ARID1A. ARID1A expression was decreased in high-risk GIST tissues. Furthermore, ARID1A knockdown in GIST cells promoted proliferation and metastasis both in vitro and in vivo, and led to reduced apoptosis and impaired cell cycle arrest. We further demonstrated that ARID1A suppresses GIST proliferation and metastasis by inhibiting MEMO1 expression and inactivating the ERK1/2 signaling pathway. Notably, this regulatory axis was observed in KIT-null GIST cells, indicating that the ARID1A-MEMO1 pathway may function independently of canonical KIT signaling. Thus, ARID1A inhibits malignant progression in GISTs, providing new insights into its role in the prevention and treatment of human GISTs and suggesting its potential as a biomarker of malignant progression in GISTs.

Humans↗

PubMed1998

Regulation of the Sex combs reduced gene in Drosophila.

The Sex combs reduced gene of the Antennapedia complex specifics the identities of the anterior thoracic and posterior head segments, including the primordium of the larval salivary gland. The Sex combs reduced transcription unit spans over 30 kb of genomic DNA, with another 40 kb of upstream cis-regulatory sequences. The pattern of Sex combs reduced transcription is set in the early embryo by the segmentation genes and is then maintained by two competing sets of proteins, the Polycomb group and the trithorax group. One of the trithorax group genes required for activation, the brahma gene, encodes an evolutionarily conserved DNA-stimulated ATPase that is part of a large protein complex. This complex facilitates the action of sequence-specific, DNA-binding proteins in regulating target genes, possibly by altering chromatin structure.

Animals↗

PubMed2001

Histone acetylation determines the developmentally regulated accessibility for T cell receptor gamma gene recombination.

Variable/diversity/joining (V[D]J) recombination of the T cell receptor (TCR) and immunoglobulin (Ig) genes is regulated by chromatin accessibility of the target locus to the recombinase in a lineage- and stage-specific manner. Histone acetylation has recently been proposed as a molecular mechanism underlying the accessibility control. Here, we investigate the role for histone acetylation in the developmentally regulated rearrangements of the mouse TCR-gamma gene, wherein predominant rearrangement is switched from Vgamma3 to Vgamma2 gene during the fetal to adult thymocyte development. Our results indicate that histone acetylation correlates with accessibility, as histone acetylation at the fetal-type Vgamma3 gene in accord with germline transcription is relatively high in fetal thymocytes, but specifically becomes low in adult thymocytes within the entirely hyperacetylated locus. Furthermore, inhibition of histone deacetylation during the development of adult bone marrow-derived thymocytes by a specific histone deacetylase inhibitor, trichostatin A, leads to elevated histone acetylation, germline transcription, cleavage, and rearrangement of the Vgamma3 gene. These data demonstrate that histone acetylation functionally determines the chromatin accessibility for V(D)J recombination in vivo and that an epigenetic modification of chromatin plays a direct role in executing a developmental switch in cell fate determination.

Acetylation↗

PubMed2005

Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies.

Epigenetic regulation of gene expression is mediated through alterations in the DNA methylation status, covalent modifications of core nucleosomal histones, rearrangement of histones, and by RNA interference. It is now abundantly clear that deregulation of epigenetic mechanisms cooperates with genetic alterations in the development and progression of cancer and leukemia. Epigenetic deregulation affects several aspects of tumor cell biology, including cell growth, cell cycle control, differentiation, DNA repair, and cell death. This raises the strong possibility that reversing deregulated epigenetic mechanisms may be an effective treatment strategy for leukemia and cancer. This treatment strategy may either be designed to separately or collectively target the specific perturbations in the epigenetic mechanisms found in human hematologic malignancies. The following review describes our current understanding of the important deregulated epigenetic mechanisms and the preclinical and clinical development of epigenetic and chromatin modifiers in the therapy of these disorders.

Chromatin↗

PubMed1995

Drosophila Polycomb-group regulated chromatin inhibits the accessibility of a trans-activator to its target DNA.

The genes of the Polycomb-group (Pc-G) are responsible for maintaining the inactive expression state of homeotic genes. They act through specific cis-regulatory DNA elements termed PREs (Pc-G Response Elements). Multimeric complexes containing the Pc-G proteins are thought to induce heterochromatin-like structures, which stably and heritably inactivate transcription. We have tested the functional role of the FAB fragment, a PRE of the bithorax complex. We find that this element behaves as an orientation dependent silencer, capable of inducing mosaic gene expression on neighboring genes. Transgenic fly lines were constructed containing a PRE adjacent to a reporter gene inducible by the yeast GAL4 trans-activator. The competition between the activator and Pc-G-containing chromatin was visualized on polytene chromosomes using immunocytochemistry. The Pc-G protein Polycomb and GAL4 have mutually exclusive binding patterns, supporting the notion that Pc-G-induced chromatin structures can prevent activators from binding to their target sequences. However, this antagonistic function can be overcome by high doses of GAL4, even in the absence of DNA replication.

Animals↗