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Histone variant macroH2A1.1 enhances non-homologous end joining-dependent DNA double-strand-break repair and reprogramming efficiency of human iPSC

ABSTRACT: Here we used RNA-Seq to gain deep mechanistic insight into the effects of macroH2A1 splicing isoforms macroH2A1.1 and macroH2A1.2 on Human Umbelical Vein Endothelial Cells (HUVEC) undergoing cell reprogramming. The process was triggered using an episome construct carrying the reprogramming factors Oct4, Sox2, Klf4, L-Myc and Lin28. RNA-seq analysis was performed on the fourth day of the reprogramming process, to investigate the role. Heatmap anlysis of top 44 differently expressed genes (DEG) revealed that macroH2A1.1, but not macroH2A1.2,increased the expression of genes involved in DNA repair response (DDR) and cell reprogramming in HUVEC. Genes exhibiting absolute fold-change values >2 and p-values <0.05 were considered differentially expressed between contrasts. Statistical differences in gene expression were assessed by the ANOVA test. Correction for multiple test was achieved by the Benjamini-Hochberg procedure. The significance threshold was set to 0.05. Ingenuity pathway analysis (IPA) identified differences in evaluating top 44 DEG involved in DDR and top 12 DEG involved in cell reprogramming showed that macroH2A1.1 verexpression enhances several pathways involved in DNa repair and acquisition of cell pluripotency.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164396 | GEO | 2021/01/08

REPOSITORIES: GEO

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Integrative CUT&Tag/RNA-Seq analysis of histone variant macroH2A1-dependent orchestration of human iPSCs reprogramming

Project description:Human-induced pluripotent stem cells (iPSCs) can be derived from adult stem cells by forced expression of defined transcription factors. This paves the way for autologous iPSC-derived therapies, which, however, are not yet considered safe. Moreover, reprogramming of somatic cells into iPSCs is an inefficient process, in the range of 0.1%–1%. The epigenetic mechanisms implicated in iPSCs reprogramming are not well understood. The substitution of canonical histone H2A with macroH2A1 histone variant exon-spliced isoforms (macroH2A1.1 and macroH2A1.2) appears as an emerging regulator of iPSCs identity. In particular, we have previously shown that overexpression of macroH2A1.1 led to a more efficient iPSCs reprogramming, by not fully defined mechanisms. Cleavage under targets and tagmentation (CUT&Tag) is a recent methodology used for robust epigenomic profiling of a limited amount of cells. Here, we employed human umbilical vein endothelial cells (HUVEC) during their reprogramming into iPSC over-expressing tagged macroH2A1.1 or macroH2A1.2, to perform for the first time an integrative CUT&Tag/RNA-Seq analysis of histone variant macroH2A1-dependent orchestration of iPSCs reprogramming. Our findings reveal a higher and more ubiquitous genome occupancy and number of differentially expressed genes orchestrated by macroH2A1.1 in HUVEC undergoing reprogramming, compared to macroH2A1.2, which involved pervasive functions related to the three embryonic germ layers and increased overlapping with CTCF, FOS, GATA2, and POLR2A transcription factor binding sites. In particular, all predicted macroH2A1.1 activating pathways were related to ectoderm/neural processes. As macroH2A1 isoforms have been previously associated with pathologies of the nervous system, our findings may provide relevant molecular insights for modeling neurodegenerative diseases using iPSCs.

2022-09-27 | GSE214013 | GEO

Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis

Project description:Obesity has tremendous impact on the health systems. Its epigenetic bases are unclear. MacroH2A1 is a variant of histone H2A, present in two alternatively exonspliced isoforms macroH2A1.1 and macroH2A1.2, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis. Their role in adipose tissue plasticity is unknown. Here we show evidence that macroH2A1.1 protein levels in the visceral adipose tissue of obese humans positively correlate with BMI, while macroH2A1.2 is nearly absent. We thus introduced a constitutive GFP-tagged transgene for macroH2A1.2 in mice and we characterized their metabolic health upon being fed a standard chow diet or a high fat diet. Despite unchanged food intake, these mice exhibit lower adipose mass and improved glucose metabolism both under a chow and an obesogenic diet. In the latter regimen, transgenic mice display smaller pancreatic islets and significantly less inflammation. Genomic and transcriptomic analyses demonstrated that association of macroH2A1.2 promoter occupancy of key adipogenic genes with their transcripts was gene specific. MacroH2A1.2 overexpression markedly inhibited adipogenesis, while overexpression of macroH2A1.1 had opposite effects. MacroH2A1.2 is an unprecedented chromatin component powerfully promoting metabolic health by modulating anti-adipogenic transcriptional networks in the differentiating adipose tissue. Strategies aiming at enhancing macroH2A1.2 expression might counteract excessive adiposity in humans.

2016-10-01 | GSE85796 | GEO

MacroH2A1 ChIP-seq from IMR90 human primary lung fibroblasts

Project description:The histone variant macroH2A1 and the poly(ADP-ribose) polymerase PARP-1 both regulate gene transcription by modulating chromatin structure and function. Of the two macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, the former is often suppressed in cancer and has the unique ability to interact with poly(ADP-ribose). Using ChIP-seq in primary lung fibroblasts, we demonstrate that macroH2A1 is incorporated into either of two spatially and functionally distinct types of chromatin; the first is marked by H3 K27 trimethylation, while the second contains a set of nine histone acetylations. MacroH2A1-regulated genes are involved in cancer progression are specifically found in macroH2A1-containing acetylated chromatin. Through the recruitment of PARP-1, macroH2A1.1 promotes the acetylation of H2B K12 and K120 which plays a key role in the regulation of macroH2A1 target genes in primary cells. The macroH2A1/PARP-1 pathway regulating H2B K12 and K120 acetylation is disrupted in cancer cells, in part, explaining macroH2A1M-bM-^@M-^Ys role in cancer suppression. Two biological replicates of the macroH2A1 ChIP and two corresponding input samples were sequenced

2014-09-15 | E-GEOD-54845 | biostudies-arrayexpress

RNA-seq from control and macroH2A1-depleted IMR90 primary human lung fibroblasts

Project description:The histone variant macroH2A1 and the poly(ADP-ribose) polymerase PARP-1 both regulate gene transcription by modulating chromatin structure and function. Of the two macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, the former is often suppressed in cancer and has the unique ability to interact with poly(ADP-ribose). Using ChIP-seq in primary lung fibroblasts, we demonstrate that macroH2A1 is incorporated into either of two spatially and functionally distinct types of chromatin; the first is marked by H3 K27 trimethylation, while the second contains a set of nine histone acetylations. MacroH2A1-regulated genes are involved in cancer progression are specifically found in macroH2A1-containing acetylated chromatin. Through the recruitment of PARP-1, macroH2A1.1 promotes the acetylation of H2B K12 and K120 which plays a key role in the regulation of macroH2A1 target genes in primary cells. The macroH2A1/PARP-1 pathway regulating H2B K12 and K120 acetylation is disrupted in cancer cells, in part, explaining macroH2A1’s role in cancer suppression. Three biological replicates of RNA-seq from cells expressing shRNA directed against macroH2A1 or luciferase as a control

2014-09-15 | E-GEOD-54846 | biostudies-arrayexpress

RNA-seq from control and macroH2A1-depleted IMR90 primary human lung fibroblasts

2014-09-15 | GSE54846 | GEO

MacroH2A1 ChIP-seq from IMR90 human primary lung fibroblasts

2014-09-15 | GSE54845 | GEO

Influence of ATM-mediated DNA damage response on genomic variation in human induced pluripotent stem cells (NimbleGen CNV)

Project description:Genome instability is a potential limitation to the research and therapeutic application of induced pluripotent stem cells (iPSCs). Observed genomic variations reflect the combined activities of DNA damage, cellular DNA damage response (DDR), and selection pressure in culture. To understand the contribution of DDR on the distribution of copy number variations (CNVs) in iPSCs, we mapped CNVs of iPSCs with mutations in the central DDR gene ATM onto genome organization landscapes defined by genome-wide replication timing profiles. We show that following reprogramming the early and late replicating genome is differentially affected by CNVs in ATM deficient iPSCs relative to wild type iPSCs. Specifically, the early replicating regions had increased CNV losses during retroviral reprogramming. This differential CNV distribution was not present after later passage or after episomal reprogramming. Comparison of different reprogramming methods in the setting of defective DNA damage response reveals unique vulnerability of early replicating open chromatin to retroviral vectors. 4 cell lines, all in duplicates

2016-03-29 | E-GEOD-78717 | biostudies-arrayexpress

Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness

Project description:Both epigenetic and splicing regulation contribute to tumor progression, but the potential links between these two levels of gene-expression regulation in pathogenesis are not well understood. Here, we report that the mouse and human RNA helicases ddx17 and ddx5 contribute to tumor-cell invasiveness by regulating alternative splicing of several DNA- and chromatin-binding factors, including the macroH2A1 histone. We show that macroH2A1 splicing isoforms differentially regulate the transcription of a set of genes involved in redox metabolism. In particular, the SOD3 gene that encodes the extracellular superoxide dismutase and plays a part in cell migration is regulated in an inverse manner by macroH2A1 splicing isoforms. These findings reveal a new regulatory pathway in which splicing factors control the expression of histone-variant isoforms that in turn drive a transcription program to switch tumor cells to an invasive phenotype. We analyzed 4T1 cells depleted or not for ddx5 and ddx17 RNA helicases using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool. Four techinical replicates were performed. We analyzed 4T1 cells depleted for ddx5 and ddx17 RNA helicases and macroH2A1.1 or macroH2A1.2 using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool. Three techinical replicates were performed.

2012-09-11 | E-GEOD-40737 | biostudies-arrayexpress

Influence of ATM-mediated DNA damage response on genomic variation in human induced pluripotent stem cells (Affymetrix expression)

2016-03-29 | E-GEOD-78716 | biostudies-arrayexpress

A map of post-translational modifications of macroH2A1 splicing variants and their interactome

Project description:The aim was to characterize PTM of macroH2A1.1 and macro H2A1.2 by LC-MS/MS to facilitate the understanding of their distinct biological functions in health and disease. Next, the interactome of macroH2A1 isoforms was investigated to elucidate whether the two variants could differentially orchestrate genome maintenance and efficiency of reprogramming, i.e., two key aspects of the induced pluripotent stem cell technology (iPSC).

2021-09-09 | PXD022968 | Pride

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