Epigenetic Loss of MLH1 Expression in Normal Human Hematopoietic Stem Cell Clones is Defined by the Promoter CpG Methylation Pattern Observed by High-Throughput Methylation Specific Sequencing

Overview

Journal Int J Stem Cell Res Ther

Date 2016 Aug 30

PMID 27570841

Citations 3

Authors

Jonathan Kenyon

Gabrielle Nickel-Meester

Yulan Qing

Gabriela Santos-Guasch

Ellen Drake

PingfuFu

Shuying Sun

Xiaodong Bai

David Wald

Eric Arts

Stanton L Gerson

Affiliations

Soon will be listed here.

Abstract

Normal human hematopoietic stem and progenitor cells (HPC) lose expression of , an important mismatch repair (MMR) pathway gene, with age. Loss of MMR leads to replication dependent mutational events and microsatellite instability observed in secondary acute myelogenous leukemia and other hematologic malignancies. Epigenetic CpG methylation upstream of the promoter is a contributing factor to acquired loss of expression in tumors of the epithelia and proximal mucosa. Using single molecule high-throughput bisulfite sequencing we have characterized the CpG methylation landscape from -938 to -337 bp upstream of the transcriptional start site (position +0), from 30 hematopoietic colony forming cell clones (CFC) either expressing or not expressing . We identify a correlation between promoter methylation and loss of expression. Additionally, using the CpG site methylation frequencies obtained in this study we were able to generate a classification algorithm capable of sorting the expressing and non-expressing CFC. Thus, as has been previously described for many tumor cell types, we report for the first time a correlation between the loss of expression and increased promoter methylation in CFC derived from CD34 selected hematopoietic stem and progenitor cells.

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