scholarly journals The TAZ2 domain of CBP/p300 directs acetylation towards H3K27 within chromatin

2020 ◽  
Author(s):  
Thomas W. Sheahan ◽  
Viktoria Major ◽  
Kimberly M. Webb ◽  
Elana Bryan ◽  
Philipp Voigt
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Enzymatic Activity ◽  
Crucial Role ◽  
Regulation Of Gene Expression ◽  
Histone H3 ◽  
Embryonic Stem ◽  
Site Specific ◽  
Lysine Residues

AbstractThe closely related acetyltransferases CBP and p300 are key regulators of gene expression in metazoans. CBP/p300 acetylate several specific lysine residues within nucleosomes, including histone H3 lysine 27 (H3K27), a hallmark of active enhancers and promoters. However, it has remained largely unclear how specificity of CBP/p300 towards H3K27 is achieved. Here we show that the TAZ2 domain of CBP is required for efficient acetylation of H3K27, while curbing activity towards other lysine residues within nucleosomes. We find that TAZ2 is a sequence-independent DNA binding module, promoting interaction between CBP and nucleosomes, thereby enhancing enzymatic activity and regulating substrate specificity of CBP. TAZ2 is further required to stabilize CBP binding to chromatin in mouse embryonic stem cells, facilitating specificity towards H3K27 and modulating gene expression. These findings reveal a crucial role of TAZ2 in regulating H3K27ac, while highlighting the importance of correct site-specific acetylation for proper regulation of gene expression.

scholarly journals Polyamines regulate gene expression by stimulating translation of histone acetyltransferase mRNAs

2020 ◽  
Vol 295 (26) ◽  
pp. 8736-8745 ◽  
Author(s):  
Akihiko Sakamoto ◽  
Yusuke Terui ◽  
Takeshi Uemura ◽  
Kazuei Igarashi ◽  
Keiko Kashiwagi
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Histone Acetyltransferases ◽  
Regulate Gene Expression ◽  
Double Stranded Rna ◽  
Protein Levels ◽  
Lysine Residues ◽  
Regulate Gene ◽  
Stimulation Of

Polyamines regulate gene expression in Escherichia coli by translationally stimulating mRNAs encoding global transcription factors. In this study, we focused on histone acetylation, one of the mechanisms of epigenetic regulation of gene expression, to attempt to clarify the role of polyamines in the regulation of gene expression in eukaryotes. We found that activities of histone acetyltransferases in both the nucleus and cytoplasm decreased significantly in polyamine-reduced mouse mammary carcinoma FM3A cells. Although protein levels of histones H3 and H4 did not change in control and polyamine-reduced cells, acetylation of histones H3 and H4 was greatly decreased in the polyamine-reduced cells. Next, we used control and polyamine-reduced cells to identify histone acetyltransferases whose synthesis is stimulated by polyamines. We found that polyamines stimulate the translation of histone acetyltransferases GCN5 and HAT1. Accordingly, GCN5- and HAT1-catalyzed acetylation of specific lysine residues on histones H3 and H4 was stimulated by polyamines. Consistent with these findings, transcription of genes required for cell proliferation was enhanced by polyamines. These results indicate that polyamines regulate gene expression by enhancing the expression of the histone acetyltransferases GCN5 and HAT1 at the level of translation. Mechanistically, polyamines enhanced the interaction of microRNA-7648-5p (miR-7648-5p) with the 5′-UTR of GCN5 mRNA, resulting in stimulation of translation due to the destabilization of the double-stranded RNA (dsRNA) between the 5′-UTR and the ORF of GCN5 mRNA. Because HAT1 mRNA has a short 5′-UTR, polyamines may enhance initiation complex formation directly on this mRNA.

scholarly journals LSD1: more than demethylation of histone lysine residues

2020 ◽  
Vol 52 (12) ◽  
pp. 1936-1947
Author(s):  
Bruno Perillo ◽  
Alfonso Tramontano ◽  
Antonio Pezone ◽  
Antimo Migliaccio
Keyword(s):  
Gene Expression ◽  
Cancer Progression ◽  
Regulation Of Gene Expression ◽  
Histone H3 ◽  
Histone Demethylase ◽  
Special Role ◽  
Histone H4 ◽  
Nonhistone Proteins ◽  
Lysine Residues ◽  
Demethylase Activity

AbstractLysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a special role in the epigenetic regulation of gene expression, as it removes methyl groups from mono- and dimethylated lysine 4 and/or lysine 9 on histone H3 (H3K4me1/2 and H3K9me1/2), behaving as a repressor or activator of gene expression, respectively. Moreover, it has been recently found to demethylate monomethylated and dimethylated lysine 20 in histone H4 and to contribute to the balance of several other methylated lysine residues in histone H3 (i.e., H3K27, H3K36, and H3K79). Furthermore, in recent years, a plethora of nonhistone proteins have been detected as targets of LSD1 activity, suggesting that this demethylase is a fundamental player in the regulation of multiple pathways triggered in several cellular processes, including cancer progression. In this review, we analyze the molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target), placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer.

scholarly journals SETDB1 plays an essential role in maintenance of gonocyte survival in pigs

Reproduction ◽  
2017 ◽  
Vol 154 (1) ◽  
pp. 23-34 ◽  
Author(s):  
Tiantian Liu ◽  
Pengfei Zhang ◽  
Tianjiao Li ◽  
Xiaoxu Chen ◽  
Zhenshuo Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Germ Cells ◽  
Theoretical Basis ◽  
Histone H3 ◽  
Embryonic Stem ◽  
Male Germ Cells ◽  
Heterochromatin Formation ◽  
Epigenetic Regulator ◽  
And Function

Histone methyltransferase SETDB1 suppresses gene expression and modulates heterochromatin formation through H3K9me2/3. Previous studies have revealed that SETDB1 catalyzes lysine 9 of histone H3 tri-methylation and plays essential roles in maintaining the survival of embryonic stem cells and spermatogonial stem cells in mice. However, the function of SETDB1 in porcine male germ cells remains unclear. The aim of the present study was to reveal the expression profile and function of SETDB1 in porcine germ cells. SETDB1 expression gradually increased during testis development. SETDB1 was strongly localized in gonocytes. Knockdown of SETDB1 gene expression led to gonocyte apoptosis and a decrease in H3K27me3, but no significant change in H3K9me3. These observations suggested that SETDB1 is a novel epigenetic regulator of porcine male germ cells, and contributes to the maintenance of gonocyte survival in pigs, probably due to the regulation of H3K27me3 rather than H3K9me3. These findings will provide a theoretical basis for the future study of epigenetic regulation of spermatogenesis.

Essential Cytoplasmic Role of the Histone Lysine Methyltransferase Setdb1 in Post-Transcriptional Regulation in Embryonic Stem Cells

2021 ◽  
Author(s):  
Roberta Rapone ◽  
Laurence Del Maestro ◽  
Costas Bouyioukos ◽  
Sonia Albini ◽  
Paola Cruz-Tapias ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Transcriptional Regulation ◽  
Mrna Stability ◽  
Regulation Of Gene Expression ◽  
Embryonic Stem ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Post Transcriptional Regulation

Abstract Embryonic stem cells (ESCs) fate is regulated both at transcriptional and post-transcriptional levels. Indeed, several studies showed that, in addition to gene transcription, mRNA stability and protein synthesis are finely tuned and strongly control the ESCs pluripotency and fate changes. An increasing number of RNA-binding proteins (RBPs) involved in post-transcriptional and translational regulation of gene expression has been identified as regulators of ESC identity. The major lysine methyltransferase Setdb1 is essential for the self-renewal and viability of ESCs. Setdb1 was primarily known to methylate the lysine 9 of histone 3 (H3K9) in the nucleus, where it regulates chromatin functions. However, Setdb1 is also massively localized in the cytoplasm, including in mouse ESCs, where its role remains unknown. Here we show that the cytoplasmic Setdb1 (cSetdb1) is essential for the survival of mESCs. Functional assays further demonstrate that cSetdb1 regulates gene expression post-transcriptionally, affecting the abundance of mRNAs and the rate of newly synthetized proteins. A yeast-two-hybrid assay shows that cSetdb1 interacts with several regulators of mRNA stability and protein translation machinery, such as the ESCs-specific E3 ubiquitin ligase and mRNA silencer Trim71/Lin41. Finally, proteomic analyses reveal that cSetdb1 is required for the integrity of Trim71 complexes involved in mRNA metabolism and translation. Altogether, our data uncover the essential cytoplasmic function of a firstly supposed nuclear “histone” lysine methyltransferase, Setdb1, and provide new insights into the cytoplasmic/post-transcriptional regulation of gene expression mediated by a key epigenetic regulator.

scholarly journals H3K27me3 is dispensable for early differentiation but required to maintain differentiated cell identity

2020 ◽  
Author(s):  
Sara A. Miller ◽  
Manashree Damle ◽  
Robert E. Kingston
Keyword(s):  
Stem Cells ◽  
Small Molecule ◽  
Normal Development ◽  
Histone H3 ◽  
Embryonic Stem ◽  
Gene Repression ◽  
Cellular Phenotype ◽  
Polycomb Repressive Complex 2 ◽  
Molecule Inhibitor

AbstractPolycomb repressive complex 2 (PRC2) catalyzes trimethylation of histone H3 on lysine 27 and is required for normal development of complex eukaryotes. The requirement for H3K27me3 in various aspects of mammalian differentiation is not clear. Though associated with repressed genes, the modification is not sufficient to induce gene repression, and in some instances is not required. To examine the role of the modification in mammalian differentiation, we blocked trimethylation of H3K27 with both a small molecule inhibitor, GSK343, and by introducing a point mutation into EZH2, the catalytic subunit of PRC2. We found that cells with substantively decreased H3K27 tri-methylation were able to differentiate, which contrasts with EZH2 null cells. Different PRC2 targets had varied requirements for H3K27me3 in repressive regulation with a subset that maintained normal levels of repression in the absence of methylation. The primary cellular phenotype when H3K27 tri-methylation was blocked was an inability of the altered cells to maintain a differentiated state when challenged. This phenotype was determined by H3K27me3 deposition both in embryonic stem cells and in the first four days of differentiation. H3K27 tri-methylation therefore was not necessary for formation of differentiated cell states but was required to maintain a stable differentiated state.

scholarly journals Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine

Science ◽  
2011 ◽  
Vol 333 (6047) ◽  
pp. 1300-1303 ◽  
Author(s):  
Shinsuke Ito ◽  
Li Shen ◽  
Qing Dai ◽  
Susan C. Wu ◽  
Leonard B. Collins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Enzymatic Activity ◽  
Genomic Dna ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Dependent Manner ◽  
Tet Proteins ◽  
Activity Dependent ◽  
Catalyzed Oxidation

5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity–dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.

scholarly journals The chromatin remodeler Ino80 mediates alternative RNAPII pausing site determination

2021 ◽  
Author(s):  
Youngseo Cheon ◽  
Sungwook Han ◽  
Taemook Kim ◽  
Daeyoup Lee
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Regulation Of Gene Expression ◽  
Nucleosome Position ◽  
Embryonic Stem ◽  
Chromatin Remodeler ◽  
Early Transcription

Promoter-proximal pausing of RNA polymerase II (RNAPII) is a critical step in early transcription elongation for the precise regulation of gene expression. Here, we provide evidence of promoter-proximal pausing-like distributions of RNAPII in S. cerevisiae. We found that genes bearing an alternative pausing site utilize Ino80p to properly localize RNAPII pausing at the first pausing site and to suppress the accumulation of RNAPII at the second pausing site, which is tightly associated with the +1 nucleosome. This alternative pausing site determination was dependent on the remodeling activity of Ino80p to modulate the +1 nucleosome position and might be controlled synergistically with Spt4p. Furthermore, we observed similar Ino80-dependent RNAPII pausing in mouse embryonic stem cells (mESCs). Based on our collective results, we hypothesize that the chromatin remodeler Ino80 plays a highly conserved role in regulating early RNAPII elongation to establish intact pausing.

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