Autonomous actions of the human growth hormone long-range enhancer

Yoo, Eung Jae; Brown, Christopher D.; Tsai, Yu-Cheng; Cooke, Nancy E.; Liebhaber, Stephen A.

doi:10.1093/nar/gkv093

Cited by 1 publication

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References 39 publications

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“…These three sites play an essential role in both the activation and the maintenance of hGH1 transcription in the somatotrope (14)(15)(16)(17) and in its maintenance in the adult (18). POU1F1 binding at these LCR sites within HSI triggers the formation of an extensive (32 kb) domain of histone acetylation throughout the hGH locus (19) and is essential for bringing the LCR in close proximity ('looping') to the hGH1 promoter (20)(21)(22). It has been demonstrated that a single-base difference between POU1F1-binding sites at the hGH1 promoter and those at HSI modifies the conformation of the POU1F1/DNA complex, suggesting that these complexes may function through differential cofactor recruitment (23).…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of a humanPOU1F1mutation associated with isolated growth hormone deficiency: a novel etiology for IGHD

Sobrier

Tsai²,

et al. 2015

Hum. Mol. Genet.

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POU1F1, a pituitary-specific POU-homeo domain transcription factor, plays an essential role in the specification of the somatotroph, lactotroph and thyrotroph lineages and in the activation of GH1, PRL and TSHβ transcription. Individuals with mutations in POU1F1 present with combined deficiency of GH, PRL and TSH. Here, we identified a heterozygous missense mutation with evidence of pathogenicity, at the POU1F1 locus, in a large family in which an isolated growth hormone deficiency segregates as an autosomal dominant trait. The corresponding p.Pro76Leu mutation maps to a conserved site within the POU1F1 transactivation domain. Bandshift assays revealed that the mutation alters wild-type POU1F1 binding to cognate sites within the hGH-LCR and hGH1 promoter, but not to sites within the PRL promoter, and it selectively increases binding affinity to sites within the hGH-LCR. Co-immunoprecipitation studies reveal that this substitution enhances interactions of POU1F1 with three of its cofactors, PITX1, LHX3a and ELK1, and that residue 76 plays a critical role in these interactions. The insertion of the mutation at the mouse Pou1f1 locus results in a dramatic loss of protein expression despite normal mRNA concentrations. Mice heterozygous for the p.Pro76Leu mutation were phenotypically normal while homozygotes demonstrated a dwarf phenotype. Overall, this study unveils the involvement of POU1F1 in dominantly inherited isolated GH deficiency and demonstrates a significant impact of the Pro76Leu mutation on DNA-binding activities, alterations in transactivating functions and interactions with cofactors. Our data further highlight difficulties in modeling human genetic disorders in the mouse despite apparent conservation of gene expression pathways and physiologic functions.

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