Aberrant DNA Hydroxymethylation Reshapes Transcription Factor Binding in Myeloid Neoplasms

Authors

Jia Li
Tingting Hong
Yue Wei
Lei Guo
Minjung Lee
Hui Yang
Caleb Class
Yaling Yang
Xiaoqiong Wang
Hua He
Stefan Siwko
M James You
Yubin Zhou
Guillermo Garcia-Manero
Yun Huang

Publication Date

6-28-2022

Journal

Clinical Epigenetics

Abstract

Epigenetic abnormalities in DNA hydroxymethylation (5hmC) have been detected in patients with myeloid neoplasms, suggesting that 5hmC might act as a valuable epigenetic mark to reflect the disease status of myeloid neoplasms. Here, we report systematic genome-wide mapping of the DNA hydroxymethylomes in over 70 patients with myeloid neoplasms. Our integrative analysis leads to the identification of distinct 5hmC signatures that can sensitively discriminate patients from healthy individuals. At the molecular level, we unveiled dynamic 5hmC changes within key transcription factor (e.g., the CEBP family) binding motifs that are essential for hematopoiesis and myeloid lineage specification. 5hmC redistribution was found to alter the genome-wide binding of CEBP-α, thereby reprogramming transcriptional outputs to affect leukemia cell survival and stemness. Taken together, we provide a comprehensive 5hmC atlas representative of myeloid neoplasms, which sets the stage for future exploration on the epigenetic etiology of hematological malignancies. Mechanistically, our study further furnishes important insights into how abnormal 5hmC distribution in patients directly interrupts the binding of transcription factors to reshape transcriptional landscapes and aggravate leukemogenesis.

Keywords

Carcinogenesis, Cell Survival, DNA Methylation, Hemato/logic Neoplasms, Humans, Leukemia, DNA hydroxymethylation; Myeloid neoplasms; TET2; Transcription factor

DOI

10.1186/s13148-022-01297-5

PMID

35765052

PMCID

PMC9241241

PubMedCentral® Posted Date

6-28-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes