The HMG-box module in FACT is critical for suppressing epigenetic variegation of heterochromatin in fission yeast
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PROVIDER: PRJNA1057767 | ENA |
REPOSITORIES: ENA
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Project description:Chromatin condensation state is the key for retrieving genetic information. High-mobility group protein (HMG) proteins exhibit DNA-binding and bending activities, playing an important role in the regulation of chromatin structure. We have shown that nucleosomes tightly packaged into heterochromatin undergo considerable dynamic histone H2A-H2B maintenance via the direct interaction between HP1/Swi6 and facilitate chromatin transcription (FACT), which is composed of the Spt16/Pob3 heterodimer and Nhp6. In this study, we analyzed the role of Nhp6, an HMG box protein, in the FACT at heterochromatin. Pob3 mutant strains showed derepressed heterochromatin-dependent gene silencing, whereas Nhp6 mutant strains did not show significant defects in chromatin regulation or gene expression, suggesting that these two modules play different roles in chromatin regulation. We expressed a protein fusing Nhp6 to the C-terminus of Pob3, which mimics the multicellular FACT component Ssrp1. The chromatin-binding activity of FACT increased with the number of Nhp6 fused to Pob3, and the heterochromatin formation rate was promoted more strongly. Furthermore, we demonstrated that this promotion of heterochromatinization inhibited the heterochromatic variegation caused by epe1+ disruption. Heterochromatic variegation can be observed in a variety of regulatory steps; however, when it is caused by fluctuations in chromatin arrangement, it can be eliminated through the strong recruitment of the FACT complex.
2024-06-12 | GSE252092 | GEO
Project description:HMG Box-Containing Protein 1 (HBP1) Protects Against Pancreatic Injury in Acute Pancreatitis but Promotes Neoplastic Progression
| PRJNA1260009 | ENA
Project description:To assess the mechanisms by which FACT depletion leads to increased sensitivity of cells to be reprogrammed, we measured the chromatin accessibility landscape using ATAC-seq following mock treatment, SSRP1 knockdown, or SUPT16H knockdown in human fibroblasts and mock, hmg-3 or hmg-4 knockdown in whole worms, and differential gene expression in hmg-3 knockout mutants or following mock, hmg-4, or spt-16 knockdown by RNAseq.
2018-08-29 | GSE98758 | GEO
Project description:Background & Aims Pancreatitis is an inflammatory disease of the exocrine pancreas and a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Previously, we identified HMG- box transcription factor 1 (HBP1) as a potential master transcription factor (TF) in the early progression of PDAC, with its expression associated with poor patient survival, underscoring its significance in pancreatic disease. However, the functional role of HBP1 in the onset and progression of acute pancreatitis (AP) remains unknown. Methods We examined HBP1 expression in human pancreatitis samples and a cerulein-induced AP mouse model. Pancreatic-specific conditional HBP1 knockout mice, with or without an oncogenic Kras mutation, were generated and compared to their littermate controls. Spatial transcriptomics and multiplexed protein assays, histological analysis, and immunostaining were utilized to characterize pathological changes. Findings from mouse models were validated using inducible HBP1-overexpressing human pancreatic ductal epithelial cells. Results HBP1 was upregulated in pancreatic exocrine cells in human chronic pancreatitis and mouse acute pancreatitis, with its expression in human chronic pancreatitis correlating with cancer presence. Pancreatic HBP1 ablation disrupted acinar homeostasis by impairing autophagic flux and exacerbating inflammation following injury. In the presence of oncogenic KRAS, HBP1 ablation delayed the formation of pancreatic intraepithelial neoplasia (PanIN), the precursor to PDAC, and slowed its progression to higher-grade lesions. Conclusions HBP1 upregulation in pancreatitis mitigates pancreatic inflammatory injury; however, in the presence of oncogenic KRAS, it facilitates PanIN progression. Thus, HBP1 serves as a critical regulator in both pancreatitis and early pancreatic neoplasia, representing a potential therapeutic target for intervening pancreatitis and PanIN progression.
2025-07-16 | GSE296582 | GEO
Project description:Position-effect variegation (PEV) is the stochastic transcriptional silencing of a gene positioned adjacent to heterochromatin. white-mottled X-chromosomal inversions in Drosophila are classic PEV models that show variegation of the eye color gene white due to its relocation next to pericentric heterochromatin. To obtain insight into the mechanism of PEV, we constructed detailed binding maps of Heterochromatin Protein 1 (HP1), a major component of heterochromatin, on white-mottled chromosomes. We find that HP1 invades euchromatin across the inversion breakpoints over ~175kb and ~30kb, causing de novo association of HP1 with 20 genes. However, HP1 binding levels in these regions show substantial local variation; white is most strongly bound by HP1 and is one of only two genes that are substantially repressed by heterochromatin. HP1 binding to the invaded region is exceptionally sensitive to the dosage of the histone methyltransferase Su(var)3-9, indicating that the de novo formed heterochromatin is relatively unstable. Our molecular maps demonstrate that heterochromatin can invade a normally euchromatic region, yet the strength of HP1 binding and effects on gene expression are highly dependent on local context. Keywords: DamID, gene expression, genetic modification.
2009-02-18 | GSE12395 | GEO
Project description:Background: With the rapid development of assisted reproductive technology (ART), although ovulation induction has made great progress, the accompanying health risks should not be ignored. Epigenetic modifications play an important role during the development of gametes and embryos. Recently, the epigenetic abnormalities caused by superovulation have attracted increasing attention. The follicle-stimulating hormone (FSH) and human menopausal gonadotropin (hMG) are common gonadotropins used for superovulation and appropriate concentration of them might be necessary. However, there is still no systematic study on the similarities and differences of DNA methylation alterations induced by superovulation with different dosage of FSH/hMG at the single cell levels. Methods: In the current study, the different doses of FSH/hMG combined with (add hcg full name here) hCG were used in C57BL/6 strain female mice to get experimental group oocytes while naturally matured oocytes and superovulated oocytes with only hCG were respectively set as controls. Single-cell level DNA methylation sequencing was carried out to all the mature oocytes to investigate the effect of superovulation with different dosage of FSH/hMG on DNA methylation during oocyte maturation. Results: In this study, we found that the hypo differentially methylated regions (DMRs) number of FSH/hMG 200 IU group both increased significantly although the whole genome methylation pattern of mature oocytes derived from superovulation were unaffected as compared with the control matured oocytes, suggesting that high dosage of FSH/hMG might lead to increased genomic methylation instability. At the same time, some of the DMRs annotated genes related to oocyte quality and embryonic development potential were disturbed in all dosage of FSH/hMG group (including Twist2, Cdk1, Ntrk2, Slc22a4, Sstr2, Wnt2, Cntnap5a, Gm2087, Slc16a7, and so on) as well as the certain ones (containing Abcc3, Zfp532, Atp1a1, Zfp804a, and so on) were impaired after high dosage of gonadotropins. We speculated that the effect of superovulation on DNA methylation during oocyte maturation might be dose-dependent to a certain extent, and such effect might affect oocyte quality and embryonic development competency. Conclusions: The current study firstly analyzed the differential impacts of different doses of gonadotropins on single-cell level DNA methylation of mouse oocytes, indicating a dose-dependent effect of superovulation with FSH/hMG and hCG on the epigenetic variations in mouse oocytes. Furthermore, some important genes that play a critical role in oocyte quality and embryo development were indicated to form the possible molecular basis of the corresponding regulation. This study laid a foundation for evaluating the safety of superovulation and highlighted the need for more and further research into ART.
2020-06-05 | GSE136730 | GEO
Project description:BACKGROUND:HMG-box proteins are a large and diverse superfamily of architectural factors that share one or more copies of a sequence- and structurally-related DNA binding domain. These proteins can modify chromatin structure by bending and unwinding DNA. HMG-box proteins can be divided into two subfamilies based on whether they recognize DNA in a sequence-dependent or sequence-independent manner. We recently identified an HMG-box protein involved in T cell development, designated TOX, which is highly conserved in humans and mice. RESULTS:We show here that based on sequence alignment, TOX best fits into the sequence-independent HMG-box family. Three other human and murine predicted proteins are identified that share a common HMG-box domain with TOX, as well as other features. The gene encoding one of these additional family members has a distinct but overlapping pattern of tissue expression when compared to TOX. In addition, we identify genes encoding predicted TOX HMG-box subfamily members in pufferfish and mosquito. CONCLUSIONS:We have identified a novel subfamily of HMG-box proteins that is related to the recently described TOX protein. The highly conserved nature of the TOX family of proteins in humans and mice and differences in the pattern of expression between family members suggest non-overlapping functions of individual proteins. In addition, our data suggest that the TOX subtype of HMG-box domain first appeared in invertebrates, was duplicated in early vertebrates and likely took on new functions in mammalian species.
| S-EPMC155677 | biostudies-literature
Project description:FACT mediates cohesin function on chromatin
| PRJNA485963 | ENA
Project description:Cohesin is a key regulator of genome architecture with roles in sister chromatid cohesion and the organisation of higher-order structures during interphase and mitosis. The recruitment and mobility of cohesin complexes on DNA are restricted by nucleosomes. Here we show that cohesin role in chromosome organization requires the histone chaperone FACT. Depletion of FACT in metaphase cells affects cohesin stability on chromatin reducing its accumulation at pericentric regions and binding on chromosome arms. Using Hi-C, we show that cohesin-dependent TAD (Topological Associated Domains)-like structures in G1 and metaphase chromosomes are disrupted in the absence of FACT. Surprisingly, sister chromatid cohesion is intact in FACT-depleted cells, although chromosome segregation failure is observed. Our results uncover a role for FACT in genome organisation by facilitating cohesin dependent compartmentalization of chromosomes into loop domains.
2019-10-11 | GSE118534 | GEO
Project description:Protein-protein interaction analysis for RNA Polymerase II and its elongation factors including: the PAF Complex, the FACT Complex, casein kinase II, DSIF, and TFIIF. These studies also characterized a number of casein kinase II phosphorylation sites on the subunits of the PAF Complex.
2015-07-20 | MSV000079197 | MassIVE