Gonadotropin gene transcription is activated by menin-mediated effects on the chromatin

Wijeweera, Andrea; Haj, Majd; Feldman, Alona; Pnueli, Lilach; Luo, Zhuojuan; Melamed, Philippa

doi:10.1016/j.bbagrm.2015.01.001

Cited by 16 publications

(28 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, H3K4me3 was found at higher levels at the most distal end of the enhancer than at the Cga promoter, partly reflecting nucleosome depletion at this promoter and possibly also reflecting distinct patterns of polymerase pausing and transcriptional consistency (26). We have already reported that, although seemingly low, the level of H3K4me3 at the Cga promoter in these cells is greater than at the repressed gonadotropin β-subunit genes and appears to be significant in activating Cga expression (27). The major distal H3K4me3 peak also is seen in ENCODE data from non-Cga-expressing cell lines, spanning ∼1 kbp and peaking in the center of the CpGI.…”

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin α-subunit gene

Pnueli

Rudnizky

Yosefzon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Since the discovery that many transcriptional enhancers are transcribed into long noncoding RNAs termed "enhancer RNAs" (eRNAs), their putative role in enhancer function has been debated. Very recent evidence has indicted that some eRNAs play a role in initiating or activating transcription, possibly by helping recruit and/or stabilize binding of the general transcription machinery to the proximal promoter of their target genes. The distal enhancer of the gonadotropin hormone α-subunit gene, chorionic gonadotropin alpha (Cga), is responsible for Cga cell-specific expression in gonadotropes and thyrotropes, and we show here that it encodes two bidirectional nonpolyadenylated RNAs whose levels are increased somewhat by exposure to gonadotropin-releasing hormone but are not necessarily linked to Cga transcriptional activity. Knockdown of the more distal eRNA led to a drop in Cga mRNA levels, initially without effect on the forward eRNA levels. With time, however, the repression on the Cga increased, and the forward eRNA levels were suppressed also. We demonstrate that the interaction of the enhancer with the promoter is lost after eRNA knockdown. Dramatic changes also were seen in the chromatin, with an increase in total histone H3 occupancy throughout this region and a virtual loss of histone H3 Lys 4 trimethylation at the promoter following the eRNA knockdown. Moreover, histone H3 Lys 27 (H3K27) acetylation, which was found at both enhancer and promoter in wild-type cells, appeared to have been replaced by H3K27 trimethylation at the enhancer. Thus, the Cga eRNA mediates the physical interaction between these genomic regions and determines the chromatin structure of the proximal promoter to allow gene expression.

show abstract

Section: Discussionmentioning

confidence: 95%

“…Pitx1 knockdown for 48 h used shRNA cloned into pSUPER-basic, and stable knockdown was achieved via pSR-GFP/neo plasmid (both from OligoEngine) expressing the shRNA (Table S1); clones were selected using G418 as in ref. 27.…”

Section: Methodsmentioning

confidence: 99%

RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin α-subunit gene

Pnueli

Rudnizky

Yosefzon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In gonadotrope cell lines, Tet1 levels were much lower in the more fully differentiated LβT2 cells in which Lhb is expressed abundantly than in the poorly differentiated αT3-1 cells in which Lhb is barely expressed ( Fig. 1B) (17), whereas levels of Tet2 and Tet3 differed less ( Fig. S1B).…”

Section: Significancementioning

confidence: 95%

“…These hormones are expressed in the pituitary gonadotropes during embryonic development, and are up-regulated during a neonatal period of proliferation, but then become quiescent until puberty, when they are reactivated by the hypothalamic gonadotropin-releasing hormone (GnRH). We have shown previously that specific chromatin modifications are involved in determining the expression of these genes in a tissue-specific or hormonally induced context (14)(15)(16)(17)(18)(19). However, the Lhb gene promoter is particularly rich in CpGs, prompting us to consider that it might be regulated by DNA methylation, and the effect of TET1 KO on ovarian development and function opened the possibility that this might be modified by TET1.Our study revealed that an N-terminal truncated TET1 is expressed in poorly differentiated proliferating gonadotropes, which appears as the more common isoform in other differentiated tissues; it is regulated by an alternative proximal promoter and repressed by estradiol (E 2 ) and dihydrotestosterone (DHT), and also by GnRH via activation of PKA.…”

mentioning

confidence: 99%

An epigenetic switch repressing Tet1 in gonadotropes activates the reproductive axis

Yosefzon

David

Tsukerman

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The TET enzymes catalyze conversion of 5-methyl cytosine (5mC) to 5-hydroxymethyl cytosine (5hmC) and play important roles during development. TET1 has been particularly well-studied in pluripotent stem cells, but -KO mice are viable, and the most marked defect is abnormal ovarian follicle development, resulting in impaired fertility. We hypothesized that TET1 might play a role in the central control of reproduction by regulating expression of the gonadotropin hormones, which are responsible for follicle development and maturation and ovarian function. We find that all three TET enzymes are expressed in gonadotrope-precursor cells, but mRNA levels decrease markedly with completion of cell differentiation, corresponding with an increase in expression of the luteinizing hormone gene, We demonstrate that poorly differentiated gonadotropes express a TET1 isoform lacking the N-terminal CXXC-domain, which represses gene expression directly and does not catalyze 5hmC at the gene promoter. We show that this isoform is also expressed in other differentiated tissues, and that it is regulated by an alternative promoter whose activity is repressed by the liganded estrogen and androgen receptors, and by the hypothalamic gonadotropin-releasing hormone through activation of PKA. Its expression is also regulated by DNA methylation, including at an upstream enhancer that is protected by TET2, to allow expression. The down-regulation of TET1 relieves its repression of the methylated gene promoter, which is then hydroxymethylated and activated by TET2 for full reproductive competence.

show abstract

“…The impact of uH2B loss on H3K4me3 at various loci was gene specific (Vethantham et al, 2012). Thus, H2B ubiquitination is not always a prerequisite for H3K4 trimethylation (Wijeweera et al, 2015).…”

Section: The Recruiters Of the H3k4 Writersmentioning

confidence: 99%

Histone H3K4 trimethylation: dynamic interplay with pre-mRNA splicing

Davie

Delcuve

2016

Biochem. Cell Biol.

View full text Add to dashboard Cite

Histone H3 lysine 4 trimethylation (H3K4me3) is often stated as a mark of transcriptionally active promoters. However, closer study of the positioning of H3K4me3 shows the mark locating primarily after the first exon at the 5' splice site and overlapping with a CpG island in mammalian cells. There are several enzyme complexes that are involved in the placement of the H3K4me3 mark, including multiple protein complexes containing SETD1A, SETD1B, and MLL1 enzymes (writers). CXXC1, which is associated with SETD1A and SETD1B, target these enzymes to unmethylated CpG islands. Lysine demethylases (KDM5 family members, erasers) demethylate H3K4me3. The H3K4me3 mark is recognized by several proteins (readers), including lysine acetyltransferase complexes, chromatin remodelers, and RNA bound proteins involved in pre-mRNA splicing. Interestingly, attenuation of H3K4me3 impacts pre-mRNA splicing, and inhibition of pre-mRNA splicing attenuates H3K4me3.

show abstract

Gonadotropin gene transcription is activated by menin-mediated effects on the chromatin

Cited by 16 publications

References 67 publications

RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin α-subunit gene

RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin α-subunit gene

An epigenetic switch repressing Tet1 in gonadotropes activates the reproductive axis

Histone H3K4 trimethylation: dynamic interplay with pre-mRNA splicing

Contact Info

Product

Resources

About