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

Jozef Madzo; Hui Liu; Alexis Rodriguez; Aparna Vasanthakumar; Sriram Sundaravel; Donne Bennett D. Caces; Timothy J. Looney; Li Zhang; Janet B. Lepore; Trisha Macrae; Robert Duszynski; Alan H. Shih; Chun Xiao Song; Miao Yu; Yiting Yu; Robert Grossman; Brigitte Raumann; Amit Verma; Chuan He; Ross L. Levine; Don Lavelle; Bruce T. Lahn; Amittha Wickrema; Lucy A. Godley

doi:10.1016/j.celrep.2013.11.044

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

Jozef Madzo, Hui Liu, Alexis Rodriguez, Aparna Vasanthakumar, Sriram Sundaravel, Donne Bennett D. Caces, Timothy J. Looney, Li Zhang, Janet B. Lepore, Trisha Macrae, Robert Duszynski, Alan H. Shih, Chun Xiao Song, Miao Yu, Yiting Yu, Robert Grossman, Brigitte Raumann, Amit Verma, Chuan He, Ross L. LevineDon Lavelle, Bruce T. Lahn, Amittha Wickrema, Lucy A. Godley

Research output: Contribution to journal › Article › peer-review

88 Scopus citations

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 language	English (US)
Pages (from-to)	231-244
Number of pages	14
Journal	Cell Reports
Volume	6
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2013.11.044
State	Published - 2014

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2013.11.044

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Madzo, J., Liu, H., Rodriguez, A., Vasanthakumar, A., Sundaravel, S., Caces, D. B. D., Looney, T. J., Zhang, L., Lepore, J. B., Macrae, T., Duszynski, R., Shih, A. H., Song, C. X., Yu, M., Yu, Y., Grossman, R., Raumann, B., Verma, A., He, C., ... Godley, L. A. (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

Madzo, J, Liu, H, Rodriguez, A, Vasanthakumar, A, Sundaravel, S, Caces, DBD, Looney, TJ, Zhang, L, Lepore, JB, Macrae, T, Duszynski, R, Shih, AH, Song, CX, Yu, M, Yu, Y, Grossman, R, Raumann, B, Verma, A, He, C, Levine, RL, Lavelle, D, Lahn, BT, Wickrema, A & Godley, LA 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

@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 Caces, {Donne Bennett D.} and Looney, {Timothy J.} and Li Zhang and Lepore, {Janet B.} and Trisha Macrae and Robert Duszynski and Shih, {Alan H.} and Song, {Chun Xiao} and Miao Yu and Yiting Yu and Robert Grossman and Brigitte Raumann and Amit Verma and Chuan He and Levine, {Ross L.} and Don Lavelle and Lahn, {Bruce T.} and Amittha Wickrema and Godley, {Lucy A.}",

note = "Funding Information: We gratefully acknowledge all of the members of the Wickrema and Godley laboratories for helpful discussions as well as constructive comments on this work from Emery Bresnick, Ursula Storb, and Vincent Marchesi. We also thank UIC MMPF members Jerry White and Bryan Zahakaylo for their assistance in running the LC-MS. This work was supported in part by NIH grants CA129831 (to L.A.G.) and CA129831-03S1 (to C.H., B.T.L., and L.A.G.), HL116336 (to A.W. and A. Verma), F32-DK092030 (to A. Vasanthakumar), and the Giving Tree Foundation (to A.W.). ",

year = "2014",

doi = "10.1016/j.celrep.2013.11.044",

language = "English (US)",

volume = "6",

pages = "231--244",

journal = "Cell Reports",

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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, Donne Bennett D.

AU - Looney, Timothy J.

AU - Zhang, Li

AU - Lepore, Janet B.

AU - Macrae, Trisha

AU - Duszynski, Robert

AU - Shih, Alan H.

AU - Song, Chun Xiao

AU - Yu, Miao

AU - Yu, Yiting

AU - Grossman, Robert

AU - Raumann, Brigitte

AU - Verma, Amit

AU - He, Chuan

AU - Levine, Ross L.

AU - Lavelle, Don

AU - Lahn, Bruce T.

AU - Wickrema, Amittha

AU - Godley, Lucy A.

N1 - Funding Information: We gratefully acknowledge all of the members of the Wickrema and Godley laboratories for helpful discussions as well as constructive comments on this work from Emery Bresnick, Ursula Storb, and Vincent Marchesi. We also thank UIC MMPF members Jerry White and Bryan Zahakaylo for their assistance in running the LC-MS. This work was supported in part by NIH grants CA129831 (to L.A.G.) and CA129831-03S1 (to C.H., B.T.L., and L.A.G.), HL116336 (to A.W. and A. Verma), F32-DK092030 (to A. Vasanthakumar), and the Giving Tree Foundation (to A.W.).

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.

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U2 - 10.1016/j.celrep.2013.11.044

DO - 10.1016/j.celrep.2013.11.044

M3 - Article

C2 - 24373966

AN - SCOPUS:84892540146

SN - 2211-1247

VL - 6

SP - 231

EP - 244

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

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

Abstract

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