TY - JOUR
T1 - Aberrant DNA hydroxymethylation reshapes transcription factor binding in myeloid neoplasms
AU - Li, Jia
AU - Hong, Tingting
AU - Wei, Yue
AU - Guo, Lei
AU - Lee, Minjung
AU - Yang, Hui
AU - Class, Caleb
AU - Yang, Yaling
AU - Wang, Xiaoqiong
AU - He, Hua
AU - Siwko, Stefan
AU - You, M. James
AU - Zhou, Yubin
AU - Garcia-Manero, Guillermo
AU - Huang, Yun
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - DNA hydroxymethylation
KW - Myeloid neoplasms
KW - TET2
KW - Transcription factor
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U2 - 10.1186/s13148-022-01297-5
DO - 10.1186/s13148-022-01297-5
M3 - Article
C2 - 35765052
AN - SCOPUS:85132984504
SN - 1868-7075
VL - 14
JO - Clinical epigenetics
JF - Clinical epigenetics
IS - 1
M1 - 81
ER -