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Histone Methylation Patterns in Acute Leukemias are Defined by Genotype Independent of the Disease Phenotype

ABSTRACT: Epigenetic mechanisms, including acetylation, phosphorylation, and methylation of nucleosomal histones, contribute greatly to physiological control of gene expression required for hematopoietic cell differentiation. Perturbations in histone methylation patterns and mutations in histone methyltransferases and demethylases are frequently identified in acute lymphoid and myeloid leukemia. Histone H3 methylation patterns on lysine 4 and 27 residues define bivalent, or poised, chromatin in the embryonic and hematopoietic stem cells. We examined how the bivalent histone methylation patterns change through differentiation from an embryonic stem cell to a hematopoietic stem cell, and followed these changes through malignant lymphoid and myeloid hematopoiesis. Using an integrative bioinformatics analysis of genome-wide histone methylation patterns, we find that a common bivalent histone methylation pattern does not exist for lymphoid or myeloid leukemia. Instead, a select subset of key hematopoietic genes retains the activating H3K4 trimethyl mark in leukemia cells when compared with hematopoietic stem cells. A close examination of genes marked for active transcription suggests that the malignant transcriptional program is dictated primarily by the cytogenetics and the mutations present in leukemia subtypes. Our findings have implications in determining the treatment for leukemia using epigenetic inhibitors, particularly for those malignancies with a mixed immunophenotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139985 | GEO | 2024/11/01

REPOSITORIES: GEO

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Project description:Collombet2016 - Lymphoid and myeloid cell specification and transdifferentiation This model is described in the article: Logical modeling of lymphoid and myeloid cell specification and transdifferentiation Samuel Collombet, Chris van Oevelen, Jose Luis Sardina Ortega, Wassim Abou-Jaoudé, Bruno Di Stefano, Morgane Thomas-Chollier, Thomas Graf, and Denis Thieffry Proceedings of the National Academy of Sciences of the United States of America Abstract: Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors, and chromatin remodelers. Using public data and data from our own molecular genetic experiments (quantitative PCR, Western blot, EMSA) or genome-wide assays (RNA-sequencing, ChIP-sequencing), we have assembled a comprehensive regulatory network encompassing the main transcription factors and signaling components involved in myeloid and lymphoid development. Focusing on B-cell and macrophage development, we defined a qualitative dynamical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knockdowns, and the reprogramming of pre-B cells into macrophages induced by the ectopic expression of specific transcription factors. The resulting network model can be used as a template for the integration of new hematopoietic differentiation and transdifferentiation data to foster our understanding of lymphoid/myeloid cell-fate decisions. This model is hosted on BioModels Database and identified by: MODEL1610240000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Histone Methylation Patterns in Acute Leukemias are Defined by Genotype Independent of the Disease Phenotype

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