title: HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
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.
  
  
  RESULTS
  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.
authors.affiliation: Hematology Division, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Sandeep N
authors.initials: SN
authors.lastname: Shah
authors.forename: Candace
authors.initials: C
authors.lastname: Kerr
authors.forename: Leslie
authors.initials: L
authors.lastname: Cope
authors.forename: Elias
authors.initials: E
authors.lastname: Zambidis
authors.forename: Cyndi
authors.initials: C
authors.lastname: Liu
authors.forename: Joelle
authors.initials: J
authors.lastname: Hillion
authors.forename: Amy
authors.initials: A
authors.lastname: Belton
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Linda M S
authors.initials: LM
authors.lastname: Resar
mesh_terms: D054337:Cell Dedifferentiation / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology*; D005786:Gene Expression Regulation / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology*; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D039904:Pluripotent Stem Cells / Q000166:cytology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D017931:DNA Primers; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors; D025741:HMGA1a Protein; C022616:thiazolyl blue