The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells

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The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells. / Wahlberg, Karin; Jiang, Jie; Rooks, Helen; Jawaid, Kiran; Matsuda, Fumihiko; Yamaguchi, Masao; Lathrop, Mark; Thein, Swee Lay; Best, Steve.

I: Blood, Vol. 114, Nr. 6, 06.08.2009, s. 1254-62.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Wahlberg, Karin ; Jiang, Jie ; Rooks, Helen ; Jawaid, Kiran ; Matsuda, Fumihiko ; Yamaguchi, Masao ; Lathrop, Mark ; Thein, Swee Lay ; Best, Steve. / The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells. I: Blood. 2009 ; Vol. 114, Nr. 6. s. 1254-62.

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TY - JOUR

T1 - The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells

AU - Wahlberg, Karin

AU - Jiang, Jie

AU - Rooks, Helen

AU - Jawaid, Kiran

AU - Matsuda, Fumihiko

AU - Yamaguchi, Masao

AU - Lathrop, Mark

AU - Thein, Swee Lay

AU - Best, Steve

PY - 2009/8/6

Y1 - 2009/8/6

N2 - HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23 is associated with elevated fetal hemoglobin levels and has pleiotropic effects on several hematologic parameters. To investigate potential regulatory activity in the region, we have measured sensitivity of the sequences to DNase I cleavage that identified 3 tissue-specific DNase I hypersensitive sites in the core intergenic interval. Chromatin immunoprecipitation with microarray (ChIP-chip) analysis showed strong histone acetylation in a defined interval of 65 kb corresponding to the core HBS1L-MYB intergenic region in primary human erythroid cells but not in non-MYB-expressing HeLa cells. ChIP-chip analysis also identified several potential cis-regulatory elements as strong GATA-1 signals that coincided with the DNase I hypersensitive sites present in MYB-expressing erythroid cells. We suggest that HMIP contains regulatory sequences that could be important in hematopoiesis by controlling MYB expression. This study provides the functional link between genetic association of HMIP with control of fetal hemoglobin and other hematologic parameters. We also present a large-scale analysis of histone acetylation as well as RNA polymerase II and GATA-1 interactions on chromosome 6q, and alpha and beta globin gene loci. The data suggest that GATA-1 regulates numerous genes of various functions on chromosome 6q.

AB - HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23 is associated with elevated fetal hemoglobin levels and has pleiotropic effects on several hematologic parameters. To investigate potential regulatory activity in the region, we have measured sensitivity of the sequences to DNase I cleavage that identified 3 tissue-specific DNase I hypersensitive sites in the core intergenic interval. Chromatin immunoprecipitation with microarray (ChIP-chip) analysis showed strong histone acetylation in a defined interval of 65 kb corresponding to the core HBS1L-MYB intergenic region in primary human erythroid cells but not in non-MYB-expressing HeLa cells. ChIP-chip analysis also identified several potential cis-regulatory elements as strong GATA-1 signals that coincided with the DNase I hypersensitive sites present in MYB-expressing erythroid cells. We suggest that HMIP contains regulatory sequences that could be important in hematopoiesis by controlling MYB expression. This study provides the functional link between genetic association of HMIP with control of fetal hemoglobin and other hematologic parameters. We also present a large-scale analysis of histone acetylation as well as RNA polymerase II and GATA-1 interactions on chromosome 6q, and alpha and beta globin gene loci. The data suggest that GATA-1 regulates numerous genes of various functions on chromosome 6q.

KW - Acetylation

KW - Chromosomes, Human, Pair 6

KW - DNA, Intergenic

KW - Deoxyribonuclease I

KW - Fetal Hemoglobin

KW - GATA1 Transcription Factor

KW - Gene Expression Regulation

KW - Genes, myb

KW - HeLa Cells

KW - Histones

KW - Humans

KW - K562 Cells

KW - Quantitative Trait Loci

KW - Regulatory Elements, Transcriptional

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1182/blood-2009-03-210146

DO - 10.1182/blood-2009-03-210146

M3 - Article

VL - 114

SP - 1254

EP - 1262

JO - Blood

JF - Blood

SN - 1528-0020

IS - 6

ER -