Expression and function of the LIM homeobox containing genes <i>Lhx3</i> and <i>Lhx4</i> in the mouse placenta

Tian, Geng; Singh, Uma; Yu, Yang; Ellsworth, Buffy S.; Hemberger, Myriam; Geyer, Rudolf; Stewart, M. David; Behringer, Richard R.; Fundele, Reinald

doi:10.1002/dvdy.21546

Cited by 7 publications

(4 citation statements)

References 92 publications

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“…These novel targets include a differentiation-associated increase in AcH3 near the gene encoding synapse defective 1 (SYDE1), which is a Rho-GTPase activating protein stimulated by glial cells missing-1, and is important for murine placentation and human trophoblast migration 28 . Decreased AcH3 binding was detected during differentiation near LIM homeobox 4 (LHX4), which is important for development of the placental labyrinth zone in mice 29 .…”

Section: Dynamic Changes In Genomic Ach3 Binding During Syncytiotrophmentioning

confidence: 99%

Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts

et al. 2020

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Cell fusion occurs when several cells combine to form a multinuclear aggregate (syncytium). In human placenta, a syncytialized trophoblast (syncytiotrophoblast) layer forms the primary interface between maternal and fetal tissue, facilitates nutrient and gas exchange, and produces hormones vital for pregnancy. Syncytiotrophoblast development occurs by differentiation of underlying progenitor cells called cytotrophoblasts, which then fuse into the syncytiotrophoblast layer. Differentiation is associated with chromatin remodeling and specific changes in gene expression mediated, at least in part, by histone acetylation. However, the epigenetic regulation of human cytotrophoblast differentiation and fusion is poorly understood. In this study, we found that human syncytiotrophoblast development was associated with deacetylation of multiple core histone residues. Chromatin immunoprecipitation sequencing revealed chromosomal regions that exhibit dynamic alterations in histone H3 acetylation during differentiation. These include regions containing genes classically associated with cytotrophoblast differentiation (TEAD4, TP63, OVOL1, CGB), as well as near genes with novel regulatory roles in trophoblast development and function, such as LHX4 and SYDE1. Prevention of histone deacetylation using both pharmacological and genetic approaches inhibited trophoblast fusion, supporting a critical role of this process for trophoblast differentiation. Finally, we identified the histone deacetylases (HDACs) HDAC1 and HDAC2 as the critical mediators driving cytotrophoblast differentiation. Collectively, these findings provide novel insights into the epigenetic mechanisms underlying trophoblast fusion during human placental development.

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Section: Dynamic Changes In Genomic Ach3 Binding During Syncytiotrophmentioning

confidence: 99%

Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts

et al. 2020

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“…HMGA1 is required for normal sperm development (Liu et al, 2003). LHX4 is involved in the formation of the pituitary and the motoneuron system and knock out of this gene results in perinatal lethality (Geng et al, 2010). PLEKHA8 knockout mice show abnormal epididymis morphology in the International Mouse Phenotyping Consortium (IMPC) data (Dickinson et al, 2016).…”

Section: Candidate Genes Under Selection In Jiangquhai Pigsmentioning

confidence: 99%

Genome-wide genotyping uncovers genetic diversity, phylogeny, signatures of selection, and population structure of Chinese Jiangquhai pigs in a global perspective1

Wang

et al. 2019

Journal of Animal Science

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Jiangquhai pigs are one of the 42 representative local breeds listed in the national livestock genetic resources conservation project of China. This breed is known for its prolificacy, desirable meat quality, and excellent adaptability to crude feed and local environments. In this study, we genotyped 105 Jiangquhai pigs from the state conservation farm using GeneSeek GGP Porcine 80K SNP chip, and explored the SNP data to unravel genetic diversity, evolutionary phylogeny, signatures of selection, and population structure of Jiangquhai pigs in a context of 33 global breeds. Five indices of observed heterozygosity, expected heterozygosity, effective population size, runs of homozygosity, and linkage disequilibrium extent indicate that the Jiangquhai breed are still rich in genetic diversity in comparison with other breeds also from East China despite the recent decline of its population size. Phylogenetic, principal component, TreeMix, and admixture analyses show that Jiangquhai pigs represent an authentic genetic resource and have close genetic relationships with East Chinese breeds, their geographical neighbors. A genome scan unravels a list of reproduction-related genes potentially under selection in Jiangquhai pigs. Using the neighbor-joining clustering approach, we reconstructed the family structure of the conservation population of Jiangquhai pigs. This finding allowed us to suggest a rotational mating scheme across the reconstructed families to reduce the risk of inbreeding depression in the population.

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“…In mice, the normal expression of the LIM (LIN-11, Isl1, and MEC-3)-homedomain transcription factor LHX3 is necessary for pituitary development and function [2][3][4][5]. In rodents, LHX3 is necessary for survival, since mice with homozygous inactivation of Lhx3 (Lhx3 −/− ) die soon after birth; their pituitaries are aplastic and lack the anterior and intermediate lobes [2,6].…”

Section: Introductionmentioning

confidence: 99%

Heterozygous LHX3 mutations may lead to a mild phenotype of combined pituitary hormone deficiency

et al. 2018

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LHX3 is an LIM domain transcription factor involved in the early steps of pituitary ontogenesis. We report here functional studies of three allelic variants, including the first heterozygous variant of LHX3 NM_178138.5(LHX3):c.587T>C (p. (Leu196Pro)) that may be responsible for a milder phenotype of hypopituitarism. Our functional studies showed that NM_178138.5(LHX3):c.587T>C (p.(Leu196Pro)) was not able to activate target promoters in vitro, as it did not bind DNA, and likely affected LHX3 function via a mechanism of haplo-insufficiency. Our study demonstrates the possibility that patients with a heterozygous variant of LHX3 may have pituitary deficiencies, with a milder phenotype than patients with homozygous variants. It is thus of vital to propose an optimal follow-up of such patients, who, until now, were considered as not being at risk of presenting pituitary deficiency. The second variant NM_178138.5(LHX3):c.622C>G (p.(Arg208Gly)), present in a homozygous state, displayed decreased transactivating ability without loss of binding capacity in vitro, concordant with in silico analysis; it should thus be considered to affect LHX3 function. In contrast, the NM_178138.5 (LHX3):c.929G>C (p.(Arg310Pro)) variant, in a heterozygous state, also predicted as deleterious in silico, proved functionally active in vitro, and should thus still be classified as a variant of unknown significance. Our study emphasizes the need for functional studies due to the limits of software-based predictions of new variants, and the possible association of a pituitary phenotype to heterozygous LHX3 variants.

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Expression and function of the LIM homeobox containing genes Lhx3 and Lhx4 in the mouse placenta

Cited by 7 publications

References 92 publications

Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts

Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts

Genome-wide genotyping uncovers genetic diversity, phylogeny, signatures of selection, and population structure of Chinese Jiangquhai pigs in a global perspective1

Heterozygous LHX3 mutations may lead to a mild phenotype of combined pituitary hormone deficiency

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