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The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

ABSTRACT: The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

PROVIDER: PRJNA628688 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11616090.fastq.gz	Fastqsanger.gz
	SRR11616091.fastq.gz	Fastqsanger.gz
	SRR11616092.fastq.gz	Fastqsanger.gz

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The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

Project description:In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltrasferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 is a critical regulator of the development of growth hormone-releasing hormone (GHRH)-producing neurons in the hypothalamus. The two distinct Mll4 mutant mouse models exhibited dwarfism, accompanied by impairment of developmental programs for GHRH-neurons. Our genome-wide studies revealed that, in the developing hypothalamus, Mll4 collaborates mainly with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 resulted in a marked reduction of transcriptionally active histone marks in the embryonic hypothalamus, which was rescued by treatment with the histone deacetylase inhibitor AR-42. Further, AR-42 treatment restored GHRH-neuronal production in Mll4 mutant mice. Together, our results suggest that the dysregulation of MLL4-directed epigenetic control of GHRH-neuronal genes is a substantial contributing factor to dwarfism in human KS.

2020-11-07 | GSE149439 | GEO

The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus.

Project description: Not available

| S-EPMC7801453 | biostudies-literature

Primary Trophoblasts treated with Corticotropin Releasing Hormone (CRH)

Project description:Primary trophoblast cells were treated with corticotropin releasing hormone (CRH) and then subjected to RNA extraction and sequencing.

2025-03-13 | GSE279747 | GEO

Primary Trophoblasts treated with Corticotropin Releasing Hormone (CRH)

Project description:Primary Trophoblasts treated with Corticotropin Releasing Hormone (CRH)

| PRJNA1174194 | ENA

MLL4-associated condensates counterbalance Polycomb-mediated nuclear mechanical stress in Kabuki Syndrome

Project description:The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depends on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However how chromatin players contribute to the assembly of transcriptional condensates has not been addressed. By interrogating the effect of KMT2D haploinsufficiency in Kabuki Syndrome, we found that MLL4 contributes in the assembly of transcriptional condensates through liquid-liquid phase separation. MLL4 loss-of-function impaired Polycomb-dependent chromatin compartmentalization, altering nuclear architecture. By releasing the nuclear mechanical stress through the inhibition of the mechano-sensor ATR, we re-established the mechano-signaling of mesenchymal stem cells and their commitment towards chondrocytes both in vitro and in vivo. This study supports the notion that in Kabuki Syndrome the haploinsufficiency of MLL4 causes an altered functional partitioning of chromatin, which determines the architecture and mechanical properties of the nucleus.

2020-09-22 | PXD021616 | Pride

Growth hormone releasing hormone analogue protects against diabetic renal injury via inhibiting oxidative stress and ferroptosis

Project description:Growth hormone releasing hormone analogue protects against diabetic renal injury via inhibiting oxidative stress and ferroptosis

| PRJNA1250393 | ENA

PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex.

Project description: Not available

| S-EPMC2729684 | biostudies-literature

An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells

Project description:Chromatin regulators control cellular differentiation by orchestrating dynamic developmental gene expression programs, and hence, malfunctions in the regulation of chromatin state contribute to both developmental disorders and disease state. Mll4 (Kmt2d), a member of the COMPASS (COMplex of Proteins ASsociated with Set1) protein family that implements histone H3 lysine 4 monomethylation (H3K4me1) at enhancers, is essential for embryonic development and functions as a pancancer tumor suppressor. We define the roles of Mll4/COMPASS and its catalytic activity in the maintenance and exit of ground-state pluripotency in murine embryonic stem cells (ESCs). Mll4 is required for ESC to exit the naive pluripotent state; however, its intrinsic catalytic activity is dispensable for this process. The depletion of the H3K4 demethylase Lsd1 (Kdm1a) restores the ability of Mll4 null ESCs to transition from naive to primed pluripotency. Thus, we define an opposing regulatory axis, wherein Lsd1 and associated co-repressors directly repress Mll4-activated gene targets. This finding has broad reaching implications for human developmental syndromes and the treatment of tumors carrying Mll4 mutations.

2018-02-01 | GSE99022 | GEO

Gonadotropin-releasing hormone 3 and gonadotropes relationships in female zebrafish pituitary revealed by single-cell transcriptomics

Project description:Gonadotropin-releasing hormone (GnRH) governs reproduction in vertebrates by regulating pituitary gonadotropins. Zebrafish, however, is an exception as gnrh3–/– fish, which lack the hypophysiotropic GnRH3, are fertile, suggesting that zebrafish utilizes a Gnrh-independent mechanism to regulate reproduction. To elucidate the role of Gnrh3 and the Gnrh-independent mechanisms that regulate the pituitary gonadotropes, we profiled the gene expression in individual pituitary cells of wild-type and gnrh–/– adult female zebrafish and identified transcriptionally defined cell types. The classical Lh and Fsh gonadotropes expressed both gonadotropin beta subunits with a ratio of 13:1 (lhb:fshb) and 40:1 (fshb:lhb), respectively. We discovered that Lh gonadotropes predominantly express genes encoding receptors for Gnrh (gnrhr2), thyroid hormone, estrogen, dopamine, and steroidogenic factor 1 (SF1). No Gnrh receptor expression was enriched in Fsh gonadotropes, instead, the expression of cholecystokinin receptor (cckrb) and galanin receptor (gal1rb) were enriched in these cells. The hereditary loss of Gnrh3 gene resulted in downregulation of fshb in Lh gonadotropes. Likewise, targeted chemogenetic ablation of Gnrh3 neurons led to a decrease in the number of fshb+/lhb+ cells. Our studies suggest that Gnrh3 directly acts on Lh gonadotropes through Gnrhr2, but the outcome of this interaction is still unknown. Gnrh3 also regulates fshb expression, probably via a non-Gnrh receptor route. Altogether, while Lh secretion and synthesis are likely regulated by multiple factors in a Gnrh-independent manner, Gnrh3 seems to play a role in the cellular organization of the pituitary in zebrafish.

2024-11-20 | GSE272806 | GEO

Growth hormone releasing hormone analogue protects against diabetic renal injury via inhibiting oxidative stress and ferroptosis

Project description:MR409 is a synthetic growth hormone-releasing hormone (GHRH) analogue. MR409 has been shown to enhance the survival rate and efficacy of islet cell transplantation in streptozotocin (STZ)-induced diabetes mice and exerts beneficial effects on cardiovascular diseases. The present study investigated the protective effects of MR409 on DB/DB and STZ-induced diabetic mice and to explore the underlying mechanisms that related to oxidative and ferroptosis. DB/DB mice or STZ combined with high fat diet were used to establish the T2D models. MR409 (15 μg/mouse/day) was subcutaneously administrated for 8 weeks. Treatment with MR409 significantly improved renal function and decreased the renal injury and fibrosis in DB/DB mice and STZ-induced mice. MR409 increased the expression of renal GHRH receptor without affecting the growth hormone level. MR409 attenuated oxidative stress, as indicating by decreasing the expressions of NADPH oxidase subunits p22phox, gp91phox, DHE oxidative fluorescence intensity, MDA and 4-HNE expression in the kidney of DB/DB mice. Meanwhile, MR409 inhibited ferroptosis in DB/DB mice, as indicated by upregulating the expressions of GPX4, Nrf2, FTH and downregulating TFR expression. Treatment with MR409 also increased the level of GSH in the kidney of DB/DB mice. Notably, MR409 activated the PPARγ and its downstream targeted gene Klotho in the kidney of the DB/DB mice. Therefore, the present study demonstrated that MR409 alleviates diabetic nephropathy (DN) via attenuating oxidative stress and ferroptosis, which provides a novel insight into the treatment for DN.

2025-09-17 | GSE294491 | GEO

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