Altering chromatin methylation patterns and the transcriptional network involved in regulation of hematopoietic stem cell fate

Abstract

Hematopoietic stem cells (HSCs) are quiescent cells with self-renewal capacity and potential multilineage development. Various molecular regulatory mechanisms such as epigenetic modifications and transcription factor (TF) networks play crucial roles in establishing a balance between self-renewal and differentiation of HSCs. Histone/ DNA methylations are important epigenetic modifications involved in transcriptional regulation of specific lineage HSCs via controlling chromatin structure and accessibility of DNA. Also, TFs contribute to either facilitation or inhibition of gene expression through binding to enhancer or promoter regions of DNA. As a result, epigenetic factors and TFs regulate the activation or repression of HSCs genes, playing a central role in normal hematopoiesis. Given the importance of histone/DNA methylation and TFs in gene expression regulation, their aberrations, including changes in HSCs-related methylation of histone/DNA and TFs (e.g., CCAAT-enhancer-binding protein α, phosphatase and tensin homolog deleted on the chromosome 10, Runt-related transcription factor 1, signal transducers and activators of transcription, and RAS family proteins) could disrupt HSCs fate. Herewith, we summarize how dysregulations in the expression of genes related to self-renewal, proliferation, and differentiation of HSCs caused by changes in epigenetic modifications and transcriptional networks lead to clonal expansion and leukemic transformation.

Antileukemic Activity and Molecular Docking Study of a Polyphenolic Extract from Coriander Seeds

“…Four receptors were selected as targets of high interest in antileukemic research and therapy ( ABL kinase, ABL1 , BCL2 , and FLT3 ) [ 51 , 52 , 53 , 54 , 55 , 56 ]. The ligand-receptor affinity and the presence of interactions among them were chosen as criteria for a ligand–pose selection.…”

“…In natural hematopoiesis, the balance of replication, apoptosis, and differentiation is achieved by the cooperation of pro-and anti-apoptotic genes. In cancer cells, this delicate equilibrium is compromised, and a number of mutations enhance anti-apoptotic gene expression, tipping the scales in favor of proliferation [ 55 ]. BCL2 is one such anti-apoptotic gene [ 56 ].…”

<p>Identification of High-Frequency Methylation Sites in RNF180 Promoter Region Affecting Expression and Their Relationship with Prognosis of Gastric Cancer</p>

“…Methylation can affect transcription through multiple mechanisms. 22 It is generally known that promoter methylation alters the structure of chromatin, 23 and has a negative effect in a variety of diseases such as metabolic abnormalities, Alzheimer, 24 aging and tumor. 25 Gene expression depends on the binding of TFs (TFs) to promoter-specific regions.…”