active chromatin
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2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Tomasz Bieluszewski ◽  
Weronika Sura ◽  
Wojciech Dziegielewski ◽  
Anna Bieluszewska ◽  
Catherine Lachance ◽  
...  

AbstractNucleosomal acetyltransferase of H4 (NuA4) is an essential transcriptional coactivator in eukaryotes, but remains poorly characterized in plants. Here, we describe Arabidopsis homologs of the NuA4 scaffold proteins Enhancer of Polycomb-Like 1 (AtEPL1) and Esa1-Associated Factor 1 (AtEAF1). Loss of AtEAF1 results in inhibition of growth and chloroplast development. These effects are stronger in the Atepl1 mutant and are further enhanced by loss of Golden2-Like (GLK) transcription factors, suggesting that NuA4 activates nuclear plastid genes alongside GLK. We demonstrate that AtEPL1 is necessary for nucleosomal acetylation of histones H4 and H2A.Z by NuA4 in vitro. These chromatin marks are diminished genome-wide in Atepl1, while another active chromatin mark, H3K9 acetylation (H3K9ac), is locally enhanced. Expression of many chloroplast-related genes depends on NuA4, as they are downregulated with loss of H4ac and H2A.Zac. Finally, we demonstrate that NuA4 promotes H2A.Z deposition and by doing so prevents spurious activation of stress response genes.


2021 ◽  
Author(s):  
R Kirtana ◽  
Soumen Manna ◽  
Samir Kumar Patra

AbstractDifferential expression of genes involved in physiological processes are a collaborative outcome of interactions among signalling molecules, downstream effectors and epigenetic modifiers, which together dictate the regulation of genes in response to specific stimuli. MLLs and KDM5A are functionally antagonistic proteins as one acts as writer and the other as eraser of the active chromatin mark, i.e., H3K4me3. KDM5A promotes EMT by occupying promoters of both epithelial and mesenchymal markers. Through this work, it is illustrated that when bound to E-cadherin promoter, KDM5A acts as a classical repressor by demethylating H3K4me3, but on mesenchymal marker promoters, it acts as a transcriptional activator by inhibiting the activity of HDACs and increasing H3K18ac. Further it is demonstrated that KDM5A occupancy enhances either MLL1 or MLL2 by physically interacting with them and that signalling pathways regulate the enzymatic activity of KDM5A probably by phosphorylation. When not active, KDM5A signals for MLL occupancy, a mechanism that can be called epigenetic signalling.


Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2723
Author(s):  
Greisha L. Ortiz-Hernandez ◽  
Evelyn S. Sanchez-Hernandez ◽  
Pedro T. Ochoa ◽  
Catherine C. Elix ◽  
Hossam R. Alkashgari ◽  
...  

Patients with prostate cancer (PCa) receiving docetaxel chemotherapy invariably develop chemoresistance. The transcription co-activator lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 and PSIP1, is upregulated in several human cancers, including PCa and promotes resistance to docetaxel and other drugs. The C-terminal region of LEDGF/p75 contains an integrase binding domain (IBD) that tethers nuclear proteins, including the HIV-1 integrase and transcription factors, to active chromatin to promote viral integration and transcription of cellular survival genes. Here, we investigated the contribution of the LEDGF/p75 IBD interactome to PCa chemoresistance. Quantitative immunoblotting revealed that LEDGF/p75 and its IBD-interacting partners are endogenously upregulated in docetaxel-resistant PCa cell lines compared to docetaxel-sensitive parental cells. Using specific human autoantibodies, we co-immunoprecipitated LEDGF/p75 with its endogenous IBD-interacting partners JPO2, menin, MLL, IWS1, ASK1, and PogZ, as well as transcription factors c-MYC and HRP2, in docetaxel-resistant cells, and confirmed their nuclear co-localization by confocal microscopy. Depletion of LEDGF/p75 and selected interacting partners robustly decreased the survival, clonogenicity, and tumorsphere formation capacity of docetaxel-resistant cells. These results implicate the LEDGF/p75 IBD interactome in PCa chemoresistance and could lead to novel therapeutic strategies targeting this protein complex for the treatment of docetaxel-resistant tumors.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Minglei Shi ◽  
Kaiqiang You ◽  
Taoyu Chen ◽  
Chao Hou ◽  
Zhengyu Liang ◽  
...  

Background Liquid-liquid phase separation (LLPS) is an important organizing principle for biomolecular condensation and chromosome compartmentalization. However, while many proteins have been reported to undergo LLPS, quantitative and global analysis of chromatin LLPS property remains absent. Results Here, by combining chromatin-associated protein pull-down, quantitative proteomics and 1,6-hexanediol (1,6-HD) treatment, we develop Hi-MS and define an anti-1,6-HD index of chromatin-associated proteins (AICAP) to quantify 1,6-HD sensitivity of chromatin-associated proteins under physiological conditions. Compared with known physicochemical properties involved in phase separation, we find that proteins with lower AICAP are associated with higher content of disordered regions, higher hydrophobic residue preference, higher mobility and higher predicted LLPS potential. We also construct BL-Hi-C libraries following 1,6-HD treatment to study the sensitivity of chromatin conformation to 1,6-HD treatment. We find that the active chromatin and high-order structures, as well as the proteins enriched in corresponding regions, are more sensitive to 1,6-HD treatment. Conclusions Our work provides a global quantitative measurement of LLPS properties of chromatin-associated proteins and higher-order chromatin structure. Hi-MS and AICAP data provide an experimental tool and quantitative resources valuable for future studies of biomolecular condensates.


2021 ◽  
Vol 22 (16) ◽  
pp. 8646
Author(s):  
Hang Yuan ◽  
Shigeki Suzuki ◽  
Shizu Hirata-Tsuchiya ◽  
Akiko Sato ◽  
Eiji Nemoto ◽  
...  

The periodontal ligament is a soft connective tissue embedded between the alveolar bone and cementum, the surface hard tissue of teeth. Periodontal ligament fibroblasts (PDLF) actively express osteo/cementogenic genes, which contribute to periodontal tissue homeostasis. However, the key factors maintaining the osteo/cementogenic abilities of PDLF remain unclear. We herein demonstrated that PPARγ was expressed by in vivo periodontal ligament tissue and its distribution pattern correlated with alkaline phosphate enzyme activity. The knockdown of PPARγ markedly reduced the osteo/cementogenic abilities of PDLF in vitro, whereas PPARγ agonists exerted the opposite effects. PPARγ was required to maintain the acetylation status of H3K9 and H3K27, active chromatin markers, and the supplementation of acetyl-CoA, a donor of histone acetylation, restored PPARγ knockdown-induced decreases in the osteo/cementogenic abilities of PDLF. An RNA-seq/ChIP-seq combined analysis identified four osteogenic transcripts, RUNX2, SULF2, RCAN2, and RGMA, in the PPARγ-dependent active chromatin region marked by H3K27ac. Furthermore, RUNX2-binding sites were selectively enriched in the PPARγ-dependent active chromatin region. Collectively, these results identified PPARγ as the key transcriptional factor maintaining the osteo/cementogenic abilities of PDLF and revealed that global H3K27ac modifications play a role in the comprehensive osteo/cementogenic transcriptional alterations mediated by PPARγ.


2021 ◽  
Author(s):  
Noa Furth ◽  
Danielle Algranati ◽  
Bareket Dassa ◽  
Olga Beresh ◽  
Vadim Fedyuk ◽  
...  

Cancer-associated mutations in genes encoding histones dramatically reshape chromatin and support tumorigenesis. Lysine to methionine substitution of residue 27 on histone H3 (K27M) is a driver mutation in high-grade pediatric gliomas, known to abrogate Polycomb Repressive Complex 2 (PRC2) activity. We applied single-molecule systems to image individual nucleosomes and delineate the combinatorial epigenetic patterns associated with H3-K27M expression. We found that chromatin marks on H3-K27M-mutant nucleosomes are dictated both by their incorporation preferences and by intrinsic properties of the mutation. Mutant nucleosomes not only preferentially bind PRC2, but also directly interact with MLL1, thus leading to genome-wide redistribution of H3K4me3. H3-K27M-mediated deregulation of both repressive and active chromatin marks leads to unbalanced 'bivalent' chromatin, which may support a poorly differentiated cellular state. This study provides evidence for a direct effect of H3-K27M oncohistone on the MLL1-H3K4me3 pathway and highlights the capability of single-molecule tools to reveal mechanisms of chromatin deregulation in cancer.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chi Zhang ◽  
Filippo Macchi ◽  
Elena Magnani ◽  
Kirsten C. Sadler

AbstractWe hypothesized that the highly controlled pattern of gene expression that is essential for liver regeneration is encoded by an epigenetic code set in quiescent hepatocytes. Here we report that epigenetic and transcriptomic profiling of quiescent and regenerating mouse livers define chromatin states that dictate gene expression and transposon repression. We integrate ATACseq and DNA methylation profiling with ChIPseq for the histone marks H3K4me3, H3K27me3 and H3K9me3 and the histone variant H2AZ to identify 6 chromatin states with distinct functional characteristics. We show that genes involved in proliferation reside in active states, but are marked with H3K27me3 and silenced in quiescent livers. We find that during regeneration, H3K27me3 is depleted from their promoters, facilitating their dynamic expression. These findings demonstrate that hepatic chromatin states in quiescent livers predict gene expression and that pro-regenerative genes are maintained in active chromatin states, but are restrained by H3K27me3, permitting a rapid and synchronized response during regeneration.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
William Jordan ◽  
Erica Larschan

Abstract Background Drosophila dosage compensation is an important model system for defining how active chromatin domains are formed. The male-specific lethal dosage compensation complex (MSLc) increases transcript levels of genes along the length of the single male X-chromosome to equalize with that expressed from the two female X-chromosomes. The strongest binding sites for MSLc cluster together in three-dimensional space largely independent of MSLc because clustering occurs in both sexes. CLAMP, a non-sex specific, ubiquitous zinc finger protein, binds synergistically with MSLc to enrich the occupancy of both factors on the male X-chromosome. Results Here, we demonstrate that CLAMP promotes the observed three-dimensional clustering of MSLc binding sites. Moreover, the X-enriched CLAMP protein more strongly promotes longer-range three-dimensional interactions on the X-chromosome than autosomes. Genome-wide, CLAMP promotes three-dimensional interactions between active chromatin regions together with other insulator proteins. Conclusion Overall, we define how long-range interactions which are modulated by a locally enriched ubiquitous transcription factor promote hyper-activation of the X-chromosome to mediate dosage compensation.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eva Höllmüller ◽  
Simon Geigges ◽  
Marie L. Niedermeier ◽  
Kai-Michael Kammer ◽  
Simon M. Kienle ◽  
...  

AbstractDecoding the role of histone posttranslational modifications (PTMs) is key to understand the fundamental process of epigenetic regulation. This is well studied for PTMs of core histones but not for linker histone H1 in general and its ubiquitylation in particular due to a lack of proper tools. Here, we report on the chemical synthesis of site-specifically mono-ubiquitylated H1.2 and identify its ubiquitin-dependent interactome on a proteome-wide scale. We show that site-specific ubiquitylation of H1 at position K64 modulates interactions with deubiquitylating enzymes and the deacetylase SIRT1. Moreover, it affects H1-dependent chromatosome assembly and phase separation resulting in a more open chromatosome conformation generally associated with a transcriptionally active chromatin state. In summary, we propose that site-specific ubiquitylation plays a general regulatory role for linker histone H1.


2021 ◽  
Author(s):  
Anne Helness ◽  
Jennifer Fraszczak ◽  
Charles Joly-Beauparlant ◽  
Halil Bagci ◽  
Christian Trahan ◽  
...  

Abstract GFI1 is a SNAG-domain, DNA binding transcriptional repressor which controls myeloid differentiation, in particular the formation of neutrophils. Here we show that GFI1 interacts with the chromodomain helicase CHD4 and other components of the “Nucleosome remodeling and deacetylase” (NuRD) complex. In granulo-monocytic precursors, GFI1, CHD4 or GFI1/CHD4 complexes occupy sites of open chromatin enriched for histone marks associated with active transcription suggesting that GFI1 recruits the NuRD complex to target genes that are regulated by active or bivalent promoters and active enhancers. Our data also show that GFI1 and GFI1/CHD4 complexes occupy promoters of different sets of genes that are either enriched for IRF1 or SPI-1 consensus sites, respectively. During neutrophil differentiation, overall chromatin closure and depletion of H3K4me2 occurs at different degrees depending on whether GFI1, CHD4 or both are present, indicating that GFI1 affects the chromatin remodeling activity of the NuRD complex. Moreover, GFI1/CHD4 complexes regulate chromatin openness and histone modifications differentially to enable regulation of target genes affecting the signaling pathways of the immune response or nucleosome organization or cellular metabolic processes.


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