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Uncoupling Histone Modification Crosstalk by Engineering Lysine Demethylase LSD1 [RNA-seq]

ABSTRACT: Biochemical crosstalk between two or more histone modifications is often observed in epigenetic enzyme regulation but its functional significance in cells has been difficult to discern. Prior enzymatic studies have revealed that Lys14 acetylation of histone H3 can inhibit Lys4 demethylation by lysine specific demethylase 1 (LSD1). Here we have engineered a mutant form of LSD1, Y391K, which renders the nucleosome demethylase activity of LSD1 insensitive to Lys14 acetylation. Y391K LSD1 knockin cells show increased repression of a set of genes associated with cellular adhesion. Chromatin profiling revealed that the cis-regulatory regions of these silenced genes display a higher level of H3 Lys14 acetylation than the baseline in unedited, parental cells. Y391K LSD1 knockin cells show diminished H3 mono-methyl Lys4 in the vicinity of these silenced genes, consistent with a role for enhanced LSD1 demethylase activity in these regions. These findings illuminate the functional consequences of disconnecting histone modification crosstalk for a key epigenetic enzyme in gene and chromatin regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243427 | GEO | 2024/05/08

REPOSITORIES: GEO

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Project description:Epigenetic deregulation plays a critical role in the pathogenesis of Acute Myeloid Leukemia. But changes in histone modification patterns at the epigenome level still remain largely unknown. Here, we analyzed alterations of histone H3 acetylation patterns in a large number of patients with AML compared to CD34+ progenitor cells. Using ChIP-Chip assays, we demonstrate that AML blasts exhibit significant changes in Histone H3 acetylation levels at more than 1000 genomic loci. Importantly, at core promoter regions losses of H3 acetlyation levels prevailed which suggested that a large number of genes is epigenetically silenced in AML. The validation of identified genes led to the discovery of Peroxiredoxin 2 (PRDX2) as a potential tumor suppressor gene in AML. Peroxiredoxin-2 (PRDX2) was silenced in most AML patients by decreased Histone H3 acetylation and in almost 20% by promoter DNA hypermethylation. Low protein expression of the antioxidant PRDX2 gene was clinically associated with a poor prognosis in AML patients. Functionally, PRDX2 acted as an inhibitor of myeloid cell growth by reducing levels of reactive oxygen species generated in response to cytokines. A high level of PRDX2 expression inhibited myc-induced murine leukemogenesis whereas loss of PRDX2 increased myeloid cell proliferation and accelerated myc-induced leukemogenesis. Taken together, we identify widespread loss of Histone H3 acetylation at core promoter regions as a signature of AML blasts. Epigenome wide analyses of histone H3 acetylation led to the identification of PRDX2 as an epigenetically silenced growth suppressor that contributed to the malignant phenotype in AML. Blasts from patients with AML (n=72) were obtained at the time of diagnosis (in a few cases at first relapse). CD34+ progenitor cells (n=17) and white blood cells (n=16) were used as control samples. Immunoprecipitations were performed for anti-acetylated Histone H3. Chromatin-IPs were amplified using ligation mediated PCR and labeled using Cy3 coupled to incorporated amino-allyl-UTP. Common reference DNA consisting of a mixture of genomic DNA from AML patients was prepared, amplified and labeled in a similar way with Cy5.

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Uncoupling Histone Modification Crosstalk by Engineering Lysine Demethylase LSD1 [RNA-seq]

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