HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers

Ralph Stadhouders; Suleyman Aktuna; Supat Thongjuea; Ali Aghajanirefah; Farzin Pourfarzad; Wilfred van IJcken; Boris Lenhard; Helen Rooks; Steve Best; Stephan Menzel; Frank Grosveld; Swee Lay Thein; Eric Soler

doi:10.1172/JCI71520

HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers

Ralph Stadhouders, Suleyman Aktuna, Supat Thongjuea, Ali Aghajanirefah, Farzin Pourfarzad, Wilfred van IJcken, Boris Lenhard, Helen Rooks, Steve Best, Stephan Menzel, Frank Grosveld, Swee Lay Thein^*, Eric Soler

^*Corresponding author for this work

Comprehensive Cancer Centre

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

151 Citations (Scopus)

Abstract

Genetic studies have identified common variants within the intergenic region (HBS1L-MYB) between GTP-binding elongation factor HBS1L and myeloblastosis oncogene MYB on chromosome 6q that are associated with elevated fetal hemoglobin (HbF) levels and alterations of other clinically important human erythroid traits. It is unclear how these noncoding sequence variants affect multiple erythrocyte characteristics. Here, we determined that several HBS1L-MYB intergenic variants affect regulatory elements that are occupied by key erythroid transcription factors within this region. These elements interact with MYB, a critical regulator of erythroid development and HbF levels. We found that several HBS1L-MYB intergenic variants reduce transcription factor binding, affecting long-range interactions with MYB and MYB expression levels. These data provide a functional explanation for the genetic association of HBS1L-MYB intergenic polymorphisms with human erythroid traits and HbF levels. Our results further designate MYB as a target for therapeutic induction of HbF to ameliorate sickle cell and beta-thalassemia disease severity.

Original language	English
Pages (from-to)	1699-1710
Number of pages	12
Journal	Journal of Clinical Investigation
Volume	124
Issue number	4
Early online date	10 Mar 2014
DOIs	https://doi.org/10.1172/JCI71520
Publication status	Published - 1 Apr 2014

Keywords

BETA-GLOBIN LOCUS
CHROMOSOME CONFORMATION CAPTURE
CAUSES HEREDITARY PERSISTENCE
GENOME-WIDE ASSOCIATION
C-MYB
GENE-EXPRESSION
ERYTHROID-DIFFERENTIATION
CHROMATIN INTERACTIONS
TRANSCRIPTION FACTORS
SPATIAL-ORGANIZATION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/JCI71520

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title = "HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers",

abstract = "Genetic studies have identified common variants within the intergenic region (HBS1L-MYB) between GTP-binding elongation factor HBS1L and myeloblastosis oncogene MYB on chromosome 6q that are associated with elevated fetal hemoglobin (HbF) levels and alterations of other clinically important human erythroid traits. It is unclear how these noncoding sequence variants affect multiple erythrocyte characteristics. Here, we determined that several HBS1L-MYB intergenic variants affect regulatory elements that are occupied by key erythroid transcription factors within this region. These elements interact with MYB, a critical regulator of erythroid development and HbF levels. We found that several HBS1L-MYB intergenic variants reduce transcription factor binding, affecting long-range interactions with MYB and MYB expression levels. These data provide a functional explanation for the genetic association of HBS1L-MYB intergenic polymorphisms with human erythroid traits and HbF levels. Our results further designate MYB as a target for therapeutic induction of HbF to ameliorate sickle cell and beta-thalassemia disease severity.",

keywords = "BETA-GLOBIN LOCUS, CHROMOSOME CONFORMATION CAPTURE, CAUSES HEREDITARY PERSISTENCE, GENOME-WIDE ASSOCIATION, C-MYB, GENE-EXPRESSION, ERYTHROID-DIFFERENTIATION, CHROMATIN INTERACTIONS, TRANSCRIPTION FACTORS, SPATIAL-ORGANIZATION",

author = "Ralph Stadhouders and Suleyman Aktuna and Supat Thongjuea and Ali Aghajanirefah and Farzin Pourfarzad and {van IJcken}, Wilfred and Boris Lenhard and Helen Rooks and Steve Best and Stephan Menzel and Frank Grosveld and Thein, {Swee Lay} and Eric Soler",

year = "2014",

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doi = "10.1172/JCI71520",

language = "English",

volume = "124",

pages = "1699--1710",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

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TY - JOUR

T1 - HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers

AU - Stadhouders, Ralph

AU - Aktuna, Suleyman

AU - Thongjuea, Supat

AU - Aghajanirefah, Ali

AU - Pourfarzad, Farzin

AU - van IJcken, Wilfred

AU - Lenhard, Boris

AU - Rooks, Helen

AU - Best, Steve

AU - Menzel, Stephan

AU - Grosveld, Frank

AU - Thein, Swee Lay

AU - Soler, Eric

PY - 2014/4/1

Y1 - 2014/4/1

N2 - Genetic studies have identified common variants within the intergenic region (HBS1L-MYB) between GTP-binding elongation factor HBS1L and myeloblastosis oncogene MYB on chromosome 6q that are associated with elevated fetal hemoglobin (HbF) levels and alterations of other clinically important human erythroid traits. It is unclear how these noncoding sequence variants affect multiple erythrocyte characteristics. Here, we determined that several HBS1L-MYB intergenic variants affect regulatory elements that are occupied by key erythroid transcription factors within this region. These elements interact with MYB, a critical regulator of erythroid development and HbF levels. We found that several HBS1L-MYB intergenic variants reduce transcription factor binding, affecting long-range interactions with MYB and MYB expression levels. These data provide a functional explanation for the genetic association of HBS1L-MYB intergenic polymorphisms with human erythroid traits and HbF levels. Our results further designate MYB as a target for therapeutic induction of HbF to ameliorate sickle cell and beta-thalassemia disease severity.

AB - Genetic studies have identified common variants within the intergenic region (HBS1L-MYB) between GTP-binding elongation factor HBS1L and myeloblastosis oncogene MYB on chromosome 6q that are associated with elevated fetal hemoglobin (HbF) levels and alterations of other clinically important human erythroid traits. It is unclear how these noncoding sequence variants affect multiple erythrocyte characteristics. Here, we determined that several HBS1L-MYB intergenic variants affect regulatory elements that are occupied by key erythroid transcription factors within this region. These elements interact with MYB, a critical regulator of erythroid development and HbF levels. We found that several HBS1L-MYB intergenic variants reduce transcription factor binding, affecting long-range interactions with MYB and MYB expression levels. These data provide a functional explanation for the genetic association of HBS1L-MYB intergenic polymorphisms with human erythroid traits and HbF levels. Our results further designate MYB as a target for therapeutic induction of HbF to ameliorate sickle cell and beta-thalassemia disease severity.

KW - BETA-GLOBIN LOCUS

KW - CHROMOSOME CONFORMATION CAPTURE

KW - CAUSES HEREDITARY PERSISTENCE

KW - GENOME-WIDE ASSOCIATION

KW - C-MYB

KW - GENE-EXPRESSION

KW - ERYTHROID-DIFFERENTIATION

KW - CHROMATIN INTERACTIONS

KW - TRANSCRIPTION FACTORS

KW - SPATIAL-ORGANIZATION

U2 - 10.1172/JCI71520

DO - 10.1172/JCI71520

M3 - Article

SN - 0021-9738

VL - 124

SP - 1699

EP - 1710

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 4

ER -

HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers

Abstract

Keywords

UN SDGs

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