HMGA1 Reprograms Somatic Cells into Pluripotent Stem Cells by Inducing Stem Cell Transcriptional Networks

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Nov 21

PMID 23166588

Citations 65

Authors

Sandeep N Shah

Candace Kerr

Leslie Cope

Elias Zambidis

Cyndi Liu

Joelle Hillion

Amy Belton

David L Huso

Linda M S Resar

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods/principal Findings: 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.

Conclusions: 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.

Citing Articles

High Mobility Group A1 Chromatin Keys: Unlocking the Genome During MPN Progression.

Resar L, Luo L Int J Mol Sci. 2025; 26(5).

PMID: 40076747 PMC: 11899949. DOI: 10.3390/ijms26052125.

HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis.

Luo L, Kim J, Herrera I, Wu S, Wu X, Park S J Clin Invest. 2025; 135(3).

PMID: 39895630 PMC: 11785931. DOI: 10.1172/JCI184442.

Receptor activity-modifying protein 1 regulates the differentiation of mouse skin fibroblasts by downregulating α-SMA expression via suppression of high mobility group AT-hook 1 to promote skin wound repair.

Song R, Ma J, Yin S, Wu Z, Liu C, Sun R Burns Trauma. 2025; 13():tkae068.

PMID: 39839760 PMC: 11750253. DOI: 10.1093/burnst/tkae068.

Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration.

Bouwman M, de Bakker D, Honkoop H, Giovou A, Versteeg D, Boender A Nat Cardiovasc Res. 2025; 4(1):64-82.

PMID: 39747457 PMC: 11738996. DOI: 10.1038/s44161-024-00588-9.

High mobility group A1 (HMGA1) promotes the tumorigenesis of colorectal cancer by increasing lipid synthesis.

Zhao Y, Liu M, Zhang L, Yang Q, Sun Q, Guo J Nat Commun. 2024; 15(1):9909.

PMID: 39548107 PMC: 11568219. DOI: 10.1038/s41467-024-54400-0.

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