Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis

Jozef Madzo, Hui Liu, Alexis Rodriguez, Aparna Vasanthakumar, Sriram Sundaravel, DonneBennettD Caces, TimothyJ Looney, Li Zhang, JanetB Lepore, Trisha Macrae, Robert Duszynski, AlanH Shih, Chun Xiao Song, Miao Yu, Yiting Yu, Robert Grossman, Brigitte Raumann, Amit K. Verma, Chuan He, RossL Levine & 4 others Don Lavelle, BruceT Lahn, Amittha Wickrema, LucyA Godley

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Hematopoietic stem cell differentiation involves the silencing of self-renewal genes and induction of a specific transcriptional program. Identification of multiple covalent cytosine modifications raises the question of how these derivatized bases influence stem cell commitment. Using a replicative primary human hematopoietic stem/progenitor cell differentiation system, we demonstrate dynamic changes of 5-hydroxymethylcytosine (5-hmC) during stem cell commitment and differentiation to the erythroid lineage. Genomic loci that maintain or gain 5-hmC density throughout erythroid differentiation contain binding sites for erythroid transcription factors and several factors not previously recognized as erythroid-specific factors. The functional importance of 5-hmC was demonstrated by impaired erythroid differentiation, with augmentation of myeloid potential, and disrupted 5-hmC patterning in leukemia patient-derived CD34+ stem/early progenitor cells with TET methylcytosine dioxygenase 2 (TET2) mutations. Thus, chemical conjugation and affinity purification of 5-hmC-enriched sequences followed by sequencing serve as resources for deciphering functional implications for gene expression during stem cell commitment and differentiation along a particular lineage.

Original languageEnglish (US)
Pages (from-to)231-244
Number of pages14
JournalCell Reports
Volume6
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Erythropoiesis
Nucleic Acid Regulatory Sequences
Stem cells
Stem Cells
Genes
Cell Differentiation
Hematopoietic Stem Cells
Dioxygenases
Cytosine
Gene expression
Purification
Leukemia
Transcription Factors
Binding Sites
5-hydroxymethylcytosine
Gene Expression
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Madzo, J., Liu, H., Rodriguez, A., Vasanthakumar, A., Sundaravel, S., Caces, D., ... Godley, L. (2014). Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis. Cell Reports, 6(1), 231-244. https://doi.org/10.1016/j.celrep.2013.11.044

Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis. / Madzo, Jozef; Liu, Hui; Rodriguez, Alexis; Vasanthakumar, Aparna; Sundaravel, Sriram; Caces, DonneBennettD; Looney, TimothyJ; Zhang, Li; Lepore, JanetB; Macrae, Trisha; Duszynski, Robert; Shih, AlanH; Song, Chun Xiao; Yu, Miao; Yu, Yiting; Grossman, Robert; Raumann, Brigitte; Verma, Amit K.; He, Chuan; Levine, RossL; Lavelle, Don; Lahn, BruceT; Wickrema, Amittha; Godley, LucyA.

In: Cell Reports, Vol. 6, No. 1, 2014, p. 231-244.

Research output: Contribution to journalArticle

Madzo, J, Liu, H, Rodriguez, A, Vasanthakumar, A, Sundaravel, S, Caces, D, Looney, T, Zhang, L, Lepore, J, Macrae, T, Duszynski, R, Shih, A, Song, CX, Yu, M, Yu, Y, Grossman, R, Raumann, B, Verma, AK, He, C, Levine, R, Lavelle, D, Lahn, B, Wickrema, A & Godley, L 2014, 'Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis', Cell Reports, vol. 6, no. 1, pp. 231-244. https://doi.org/10.1016/j.celrep.2013.11.044
Madzo, Jozef ; Liu, Hui ; Rodriguez, Alexis ; Vasanthakumar, Aparna ; Sundaravel, Sriram ; Caces, DonneBennettD ; Looney, TimothyJ ; Zhang, Li ; Lepore, JanetB ; Macrae, Trisha ; Duszynski, Robert ; Shih, AlanH ; Song, Chun Xiao ; Yu, Miao ; Yu, Yiting ; Grossman, Robert ; Raumann, Brigitte ; Verma, Amit K. ; He, Chuan ; Levine, RossL ; Lavelle, Don ; Lahn, BruceT ; Wickrema, Amittha ; Godley, LucyA. / Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis. In: Cell Reports. 2014 ; Vol. 6, No. 1. pp. 231-244.
@article{9b61bc12a7f5423383aec4540259ebcd,
title = "Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis",
abstract = "Hematopoietic stem cell differentiation involves the silencing of self-renewal genes and induction of a specific transcriptional program. Identification of multiple covalent cytosine modifications raises the question of how these derivatized bases influence stem cell commitment. Using a replicative primary human hematopoietic stem/progenitor cell differentiation system, we demonstrate dynamic changes of 5-hydroxymethylcytosine (5-hmC) during stem cell commitment and differentiation to the erythroid lineage. Genomic loci that maintain or gain 5-hmC density throughout erythroid differentiation contain binding sites for erythroid transcription factors and several factors not previously recognized as erythroid-specific factors. The functional importance of 5-hmC was demonstrated by impaired erythroid differentiation, with augmentation of myeloid potential, and disrupted 5-hmC patterning in leukemia patient-derived CD34+ stem/early progenitor cells with TET methylcytosine dioxygenase 2 (TET2) mutations. Thus, chemical conjugation and affinity purification of 5-hmC-enriched sequences followed by sequencing serve as resources for deciphering functional implications for gene expression during stem cell commitment and differentiation along a particular lineage.",
author = "Jozef Madzo and Hui Liu and Alexis Rodriguez and Aparna Vasanthakumar and Sriram Sundaravel and DonneBennettD Caces and TimothyJ Looney and Li Zhang and JanetB Lepore and Trisha Macrae and Robert Duszynski and AlanH Shih and Song, {Chun Xiao} and Miao Yu and Yiting Yu and Robert Grossman and Brigitte Raumann and Verma, {Amit K.} and Chuan He and RossL Levine and Don Lavelle and BruceT Lahn and Amittha Wickrema and LucyA Godley",
year = "2014",
doi = "10.1016/j.celrep.2013.11.044",
language = "English (US)",
volume = "6",
pages = "231--244",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis

AU - Madzo, Jozef

AU - Liu, Hui

AU - Rodriguez, Alexis

AU - Vasanthakumar, Aparna

AU - Sundaravel, Sriram

AU - Caces, DonneBennettD

AU - Looney, TimothyJ

AU - Zhang, Li

AU - Lepore, JanetB

AU - Macrae, Trisha

AU - Duszynski, Robert

AU - Shih, AlanH

AU - Song, Chun Xiao

AU - Yu, Miao

AU - Yu, Yiting

AU - Grossman, Robert

AU - Raumann, Brigitte

AU - Verma, Amit K.

AU - He, Chuan

AU - Levine, RossL

AU - Lavelle, Don

AU - Lahn, BruceT

AU - Wickrema, Amittha

AU - Godley, LucyA

PY - 2014

Y1 - 2014

N2 - Hematopoietic stem cell differentiation involves the silencing of self-renewal genes and induction of a specific transcriptional program. Identification of multiple covalent cytosine modifications raises the question of how these derivatized bases influence stem cell commitment. Using a replicative primary human hematopoietic stem/progenitor cell differentiation system, we demonstrate dynamic changes of 5-hydroxymethylcytosine (5-hmC) during stem cell commitment and differentiation to the erythroid lineage. Genomic loci that maintain or gain 5-hmC density throughout erythroid differentiation contain binding sites for erythroid transcription factors and several factors not previously recognized as erythroid-specific factors. The functional importance of 5-hmC was demonstrated by impaired erythroid differentiation, with augmentation of myeloid potential, and disrupted 5-hmC patterning in leukemia patient-derived CD34+ stem/early progenitor cells with TET methylcytosine dioxygenase 2 (TET2) mutations. Thus, chemical conjugation and affinity purification of 5-hmC-enriched sequences followed by sequencing serve as resources for deciphering functional implications for gene expression during stem cell commitment and differentiation along a particular lineage.

AB - Hematopoietic stem cell differentiation involves the silencing of self-renewal genes and induction of a specific transcriptional program. Identification of multiple covalent cytosine modifications raises the question of how these derivatized bases influence stem cell commitment. Using a replicative primary human hematopoietic stem/progenitor cell differentiation system, we demonstrate dynamic changes of 5-hydroxymethylcytosine (5-hmC) during stem cell commitment and differentiation to the erythroid lineage. Genomic loci that maintain or gain 5-hmC density throughout erythroid differentiation contain binding sites for erythroid transcription factors and several factors not previously recognized as erythroid-specific factors. The functional importance of 5-hmC was demonstrated by impaired erythroid differentiation, with augmentation of myeloid potential, and disrupted 5-hmC patterning in leukemia patient-derived CD34+ stem/early progenitor cells with TET methylcytosine dioxygenase 2 (TET2) mutations. Thus, chemical conjugation and affinity purification of 5-hmC-enriched sequences followed by sequencing serve as resources for deciphering functional implications for gene expression during stem cell commitment and differentiation along a particular lineage.

UR - http://www.scopus.com/inward/record.url?scp=84892540146&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892540146&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2013.11.044

DO - 10.1016/j.celrep.2013.11.044

M3 - Article

VL - 6

SP - 231

EP - 244

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 1

ER -