Cargando…

Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element

Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we de...

Descripción completa

Detalles Bibliográficos
Autores principales: Huang, Peng, Keller, Cheryl A., Giardine, Belinda, Grevet, Jeremy D., Davies, James O.J., Hughes, Jim R., Kurita, Ryo, Nakamura, Yukio, Hardison, Ross C., Blobel, Gerd A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647940/
https://www.ncbi.nlm.nih.gov/pubmed/28916711
http://dx.doi.org/10.1101/gad.303461.117
_version_ 1783272319979880448
author Huang, Peng
Keller, Cheryl A.
Giardine, Belinda
Grevet, Jeremy D.
Davies, James O.J.
Hughes, Jim R.
Kurita, Ryo
Nakamura, Yukio
Hardison, Ross C.
Blobel, Gerd A.
author_facet Huang, Peng
Keller, Cheryl A.
Giardine, Belinda
Grevet, Jeremy D.
Davies, James O.J.
Hughes, Jim R.
Kurita, Ryo
Nakamura, Yukio
Hardison, Ross C.
Blobel, Gerd A.
author_sort Huang, Peng
collection PubMed
description Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled β-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (γ) and adult (δ and β) globin genes (encompassing the HBBP1 and BGLT3 noncoding genes) and two distal chromosomal sites (HS5 and 3′HS1) that flank the locus. In contrast, in adult cells, the HBBP1–BGLT3 region contacts the embryonic ε-globin gene, physically separating the fetal globin genes from the enhancer (locus control region [LCR]). Deletion of the HBBP1 region in adult cells alters contact landscapes in ways more closely resembling those of fetal cells, including increased LCR–γ-globin contacts. These changes are accompanied by strong increases in γ-globin transcription. Notably, the effects of HBBP1 removal on chromatin architecture and gene expression closely mimic those of deleting the fetal globin repressor BCL11A, implicating BCL11A in the function of the HBBP1 region. Our results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new cis control elements.
format Online
Article
Text
id pubmed-5647940
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Cold Spring Harbor Laboratory Press
record_format MEDLINE/PubMed
spelling pubmed-56479402018-02-15 Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element Huang, Peng Keller, Cheryl A. Giardine, Belinda Grevet, Jeremy D. Davies, James O.J. Hughes, Jim R. Kurita, Ryo Nakamura, Yukio Hardison, Ross C. Blobel, Gerd A. Genes Dev Research Paper Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled β-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (γ) and adult (δ and β) globin genes (encompassing the HBBP1 and BGLT3 noncoding genes) and two distal chromosomal sites (HS5 and 3′HS1) that flank the locus. In contrast, in adult cells, the HBBP1–BGLT3 region contacts the embryonic ε-globin gene, physically separating the fetal globin genes from the enhancer (locus control region [LCR]). Deletion of the HBBP1 region in adult cells alters contact landscapes in ways more closely resembling those of fetal cells, including increased LCR–γ-globin contacts. These changes are accompanied by strong increases in γ-globin transcription. Notably, the effects of HBBP1 removal on chromatin architecture and gene expression closely mimic those of deleting the fetal globin repressor BCL11A, implicating BCL11A in the function of the HBBP1 region. Our results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new cis control elements. Cold Spring Harbor Laboratory Press 2017-08-15 /pmc/articles/PMC5647940/ /pubmed/28916711 http://dx.doi.org/10.1101/gad.303461.117 Text en © 2017 Huang et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Huang, Peng
Keller, Cheryl A.
Giardine, Belinda
Grevet, Jeremy D.
Davies, James O.J.
Hughes, Jim R.
Kurita, Ryo
Nakamura, Yukio
Hardison, Ross C.
Blobel, Gerd A.
Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element
title Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element
title_full Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element
title_fullStr Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element
title_full_unstemmed Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element
title_short Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element
title_sort comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647940/
https://www.ncbi.nlm.nih.gov/pubmed/28916711
http://dx.doi.org/10.1101/gad.303461.117
work_keys_str_mv AT huangpeng comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement
AT kellercheryla comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement
AT giardinebelinda comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement
AT grevetjeremyd comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement
AT daviesjamesoj comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement
AT hughesjimr comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement
AT kuritaryo comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement
AT nakamurayukio comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement
AT hardisonrossc comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement
AT blobelgerda comparativeanalysisofthreedimensionalchromosomalarchitectureidentifiesanovelfetalhemoglobinregulatoryelement