HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.

<h4>Background</h4>Although recent studies have identified genes expressed in human embryonic stem cells (hESCs) that induce pluripotency, the molecular underpinnings of normal stem cell function remain poorly understood. The high mobility group A1 (HMGA1) gene is highly expressed in hES...

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Autores principales:	Sandeep N Shah, Candace Kerr, Leslie Cope, Elias Zambidis, Cyndi Liu, Joelle Hillion, Amy Belton, David L Huso, Linda M S Resar
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bf1d8137a917472cac9e7e1d97cda020
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spelling	oai:doaj.org-article:bf1d8137a917472cac9e7e1d97cda0202021-11-18T08:08:37ZHMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.1932-620310.1371/journal.pone.0048533https://doaj.org/article/bf1d8137a917472cac9e7e1d97cda0202012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23166588/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Although recent studies have identified genes expressed in human embryonic stem cells (hESCs) that induce pluripotency, the molecular underpinnings of normal stem cell function remain poorly understood. The high mobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly differentiated, stem-like cancers; however, its role in these settings has been unclear.<h4>Methods/principal findings</h4>We show that HMGA1 is highly expressed in fully reprogrammed iPSCs and hESCs, with intermediate levels in ECCs and low levels in fibroblasts. When hESCs are induced to differentiate, HMGA1 decreases and parallels that of other pluripotency factors. Conversely, forced expression of HMGA1 blocks differentiation of hESCs. We also discovered that HMGA1 enhances cellular reprogramming of somatic cells to iPSCs together with the Yamanaka factors (OCT4, SOX2, KLF4, cMYC - OSKM). HMGA1 increases the number and size of iPSC colonies compared to OSKM controls. Surprisingly, there was normal differentiation in vitro and benign teratoma formation in vivo of the HMGA1-derived iPSCs. During the reprogramming process, HMGA1 induces the expression of pluripotency genes, including SOX2, LIN28, and cMYC, while knockdown of HMGA1 in hESCs results in the repression of these genes. Chromatin immunoprecipitation shows that HMGA1 binds to the promoters of these pluripotency genes in vivo. In addition, interfering with HMGA1 function using a short hairpin RNA or a dominant-negative construct blocks cellular reprogramming to a pluripotent state.<h4>Conclusions</h4>Our findings demonstrate for the first time that HMGA1 enhances cellular reprogramming from a somatic cell to a fully pluripotent stem cell. These findings identify a novel role for HMGA1 as a key regulator of the stem cell state by inducing transcriptional networks that drive pluripotency. Although further studies are needed, these HMGA1 pathways could be exploited in regenerative medicine or as novel therapeutic targets for poorly differentiated, stem-like cancers.Sandeep N ShahCandace KerrLeslie CopeElias ZambidisCyndi LiuJoelle HillionAmy BeltonDavid L HusoLinda M S ResarPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e48533 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sandeep N Shah Candace Kerr Leslie Cope Elias Zambidis Cyndi Liu Joelle Hillion Amy Belton David L Huso Linda M S Resar HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
description	<h4>Background</h4>Although recent studies have identified genes expressed in human embryonic stem cells (hESCs) that induce pluripotency, the molecular underpinnings of normal stem cell function remain poorly understood. The high mobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly differentiated, stem-like cancers; however, its role in these settings has been unclear.<h4>Methods/principal findings</h4>We show that HMGA1 is highly expressed in fully reprogrammed iPSCs and hESCs, with intermediate levels in ECCs and low levels in fibroblasts. When hESCs are induced to differentiate, HMGA1 decreases and parallels that of other pluripotency factors. Conversely, forced expression of HMGA1 blocks differentiation of hESCs. We also discovered that HMGA1 enhances cellular reprogramming of somatic cells to iPSCs together with the Yamanaka factors (OCT4, SOX2, KLF4, cMYC - OSKM). HMGA1 increases the number and size of iPSC colonies compared to OSKM controls. Surprisingly, there was normal differentiation in vitro and benign teratoma formation in vivo of the HMGA1-derived iPSCs. During the reprogramming process, HMGA1 induces the expression of pluripotency genes, including SOX2, LIN28, and cMYC, while knockdown of HMGA1 in hESCs results in the repression of these genes. Chromatin immunoprecipitation shows that HMGA1 binds to the promoters of these pluripotency genes in vivo. In addition, interfering with HMGA1 function using a short hairpin RNA or a dominant-negative construct blocks cellular reprogramming to a pluripotent state.<h4>Conclusions</h4>Our findings demonstrate for the first time that HMGA1 enhances cellular reprogramming from a somatic cell to a fully pluripotent stem cell. These findings identify a novel role for HMGA1 as a key regulator of the stem cell state by inducing transcriptional networks that drive pluripotency. Although further studies are needed, these HMGA1 pathways could be exploited in regenerative medicine or as novel therapeutic targets for poorly differentiated, stem-like cancers.
format	article
author	Sandeep N Shah Candace Kerr Leslie Cope Elias Zambidis Cyndi Liu Joelle Hillion Amy Belton David L Huso Linda M S Resar
author_facet	Sandeep N Shah Candace Kerr Leslie Cope Elias Zambidis Cyndi Liu Joelle Hillion Amy Belton David L Huso Linda M S Resar
author_sort	Sandeep N Shah
title	HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
title_short	HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
title_full	HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
title_fullStr	HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
title_full_unstemmed	HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
title_sort	hmga1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/bf1d8137a917472cac9e7e1d97cda020
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HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.

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