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Visualization and Sequencing of Accessible Chromatin Reveals Cell Cycle and Post-HDAC inhibitor Treatment Dynamics

ABSTRACT: Chromatin accessibility in the nucleus is a predictor of gene expression, cell division and cell type specificity. NicE-viewSeq (Nicking Enzyme assisted viewing and Sequencing) allows accessible chromatin visualization and sequencing with lower mitochondrial DNA and duplicated sequences compared to ATACsee. Using NicE-viewSeq we interrogated cell cycle G1, S and G2M specific accessible chromatin in mammalian cells. Despite DNA replication and subsequent condensation of chromatin to chromosome, chromatin accessibility remained subtly altered and generally preserved. Genome-wide alteration of accessibility for TSS and enhancer gradually decreased as the cell progressed from G1 to G2M, with distinctive differential accessibility near consensus transcription factors sites. Inhibition of histone deacetylase promoted accessible chromatin of the gene body, correlating with apoptotic gene expression. In addition, reduced chromatin accessibility for MYC oncogene pathway correlated with gene down regulation. Surprisingly, repetitive RNA expression remained unaltered following histone acetylation mediated increased accessibility. Therefore, we suggest that subtle changes in chromatin accessibility is a prerequisite during cell cycle and histone deacetylase inhibitor mediated therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139253 | GEO | 2020/09/09

REPOSITORIES: GEO

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Project description:Lymphocyte activation and effector state differentiation critically depend on integration of multiple signals, including those from antigen, co-stimulatory ligand and cytokine receptors. Thus, discovery of molecular components and mechanisms underlying signal integration is vital for the understanding and control of adaptive immune responses. Stimulation of antigen receptors in lymphocytes leads to the activation of NFAT family transcription factors (TFs) as well as the inducible expression of the immune-selective IRFs, IRF4 and IRF8; the latter are differentially controlled by co-stimulatory ligand and cytokine receptor signaling. Despite their major overlapping functions in lymphocyte activation and differentiation, it has remained enigmatic if NFATs can perform signal integration with IRF4 and IRF8, via their cooperative assembly on composite genomic regulatory elements. Composite elements (CEs) provide a powerful means of signal integration by inducible TFs and despite their clear importance, CEs arguably remain the least explored elements within cis-regulomes. To test the above hypothesis, we deployed a generalizable computational strategy, which revealed a stereospecific NFAT-IRF composite element (NICE) motif that was enriched within active chromatin regions (H3K27Ac) of activated B and T lymphocytes. NICE containing DNA sequences promoted cooperative binding of NFATs with IRF4 or IRF8. Genomic analyses in activated B cells revealed co-dependent genes that undergo activation or repression and contain NICE motifs in their regulatory regions. Notably, NFATc2 and IRF8 form a positive feedforward loop and coordinately repress the Prdm1 gene by binding a NICE motif in a phylogenetically conserved region, thereby inhibiting extrafollicular plasma cell differentiation and promoting the germinal center fate of activated B cells. The NICE motif is also enriched in DNA sequences located in accessible chromatin of human lymphocytes, suggesting evolutionary conservation of its function. The cooperative assembly of NFAT family members with IRF4 and IRF8 on NICE motifs reveals a new genomic control mechanism that enables signal integration during lymphocyte activation and differentiation.

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Visualization and Sequencing of Accessible Chromatin Reveals Cell Cycle and Post-HDAC inhibitor Treatment Dynamics

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