Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development

Regulatory elements are more evolutionarily conserved and provide a larger mutational target than coding regions of the human genome, suggesting that mutations in non-coding regions contribute significantly to development and disease. Using a computational approach to predict gene regulatory enhance...

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Main Authors:	Haliburton, Genevieve D. E., McKinsey, Gabriel L., Pollard, Katherine S.
Format:	Online
Language:	English
Published:	Springer Berlin Heidelberg 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701781/

id	pubmed-4701781
recordtype	oai_dc
spelling	pubmed-47017812016-01-11 Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development Haliburton, Genevieve D. E. McKinsey, Gabriel L. Pollard, Katherine S. Original Article Regulatory elements are more evolutionarily conserved and provide a larger mutational target than coding regions of the human genome, suggesting that mutations in non-coding regions contribute significantly to development and disease. Using a computational approach to predict gene regulatory enhancers, we found that many known and predicted embryonic enhancers cluster in genomic loci harboring development-associated genes. One of the densest clusters of predicted enhancers in the human genome is near the genes GMDS and FOXC1. GMDS encodes a short-chain mannose dehydrogenase enzyme involved in the regulation of hindbrain neural migration, and FOXC1 encodes a developmental transcription factor required for brain, heart, and eye development. We experimentally validate four novel enhancers in this locus and demonstrate that these enhancers show consistent activity during embryonic development in domains that overlap with the expression of FOXC1 and GMDS. These four enhancers contain binding motifs for several transcription factors, including the ZIC family of transcription factors. Removal of the ZIC binding sites significantly alters enhancer activity in three of these enhancers, reducing expression in the eye, hindbrain, and limb, suggesting a mechanism whereby ZIC family members may transcriptionally regulate FOXC1 and/or GMDS expression. Our findings uncover novel enhancer regions that may control transcription in a topological domain important for embryonic development. Springer Berlin Heidelberg 2015-09-17 2016 /pmc/articles/PMC4701781/ /pubmed/26382291 http://dx.doi.org/10.1007/s10048-015-0458-9 Text en © The Author(s) 2015 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Haliburton, Genevieve D. E. McKinsey, Gabriel L. Pollard, Katherine S.
spellingShingle	Haliburton, Genevieve D. E. McKinsey, Gabriel L. Pollard, Katherine S. Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development
author_facet	Haliburton, Genevieve D. E. McKinsey, Gabriel L. Pollard, Katherine S.
author_sort	Haliburton, Genevieve D. E.
title	Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development
title_short	Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development
title_full	Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development
title_fullStr	Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development
title_full_unstemmed	Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development
title_sort	disruptions in a cluster of computationally identified enhancers near foxc1 and gmds may influence brain development
description	Regulatory elements are more evolutionarily conserved and provide a larger mutational target than coding regions of the human genome, suggesting that mutations in non-coding regions contribute significantly to development and disease. Using a computational approach to predict gene regulatory enhancers, we found that many known and predicted embryonic enhancers cluster in genomic loci harboring development-associated genes. One of the densest clusters of predicted enhancers in the human genome is near the genes GMDS and FOXC1. GMDS encodes a short-chain mannose dehydrogenase enzyme involved in the regulation of hindbrain neural migration, and FOXC1 encodes a developmental transcription factor required for brain, heart, and eye development. We experimentally validate four novel enhancers in this locus and demonstrate that these enhancers show consistent activity during embryonic development in domains that overlap with the expression of FOXC1 and GMDS. These four enhancers contain binding motifs for several transcription factors, including the ZIC family of transcription factors. Removal of the ZIC binding sites significantly alters enhancer activity in three of these enhancers, reducing expression in the eye, hindbrain, and limb, suggesting a mechanism whereby ZIC family members may transcriptionally regulate FOXC1 and/or GMDS expression. Our findings uncover novel enhancer regions that may control transcription in a topological domain important for embryonic development.
publisher	Springer Berlin Heidelberg
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701781/
_version_	1613520177350049792

Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development

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