Multifaceted Targeting of the Chromatin Mediates Gonadotropin-Releasing Hormone Effects on Gene Expression in the Gonadotrope

Melamed, Philippa; Haj, Majd; Yosefzon, Yahav; Rudnizky, Sergei; Wijeweera, Andrea; Pnueli, Lilach; Kaplan, Ariel

doi:10.3389/fendo.2018.00058

Cited by 25 publications

(18 citation statements)

References 97 publications

(130 reference statements)

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“…In a wider perspective, mobile nucleosomes may be exploited to facilitate distinct outcomes when incorporated into specific genomic regions during different biological contexts. H2A.Z was shown to localize at regions other than gene promoters, among them enhancer regions (54), regions of heterochromatin (29), and DNA damage sites (55). As these processes require extensive DNA accessibility to maintain important cellular activities, it is likely that H2A.Z incorporation plays a role in establishing the long-term changes that self-sustain the basal accessibility of regions of DNA for prolonged periods.…”

Section: Discussionmentioning

confidence: 99%

The base pair-scale diffusion of nucleosomes modulates binding of transcription factors

Rudnizky

Khamis

Malik

et al. 2019

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

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The structure of promoter chromatin determines the ability of transcription factors (TFs) to bind to DNA and therefore has a profound effect on the expression levels of genes. However, the role of spontaneous nucleosome movements in this process is not fully understood. Here, we developed a single-molecule optical tweezers assay capable of simultaneously characterizing the base pair-scale diffusion of a nucleosome on DNA and the binding of a TF, using the luteinizing hormone β subunit gene (Lhb) promoter and Egr-1 as a model system. Our results demonstrate that nucleosomes undergo confined diffusion, and that the incorporation of the histone variant H2A.Z serves to partially relieve this confinement, inducing a different type of nucleosome repositioning. The increase in diffusion leads to exposure of a TF's binding site and facilitates its association with the DNA, which, in turn, biases the subsequent movement of the nucleosome. Our findings suggest the use of mobile nucleosomes as a general transcriptional regulatory mechanism.nucleosomes | transcription factors | chromatin | optical tweezers P ackaging of the DNA into chromatin reduces its accessibility to regulatory proteins, such as transcription factors (TFs) and RNA polymerase (RNAP), making the structure and dynamics of nucleosomes an essential part of gene expression regulation in higher organisms (1, 2). Although atomic-resolution structures of the nucleosome reveal strong contacts between the histone core and the DNA (3), evidence has accumulated indicating that these interactions are often disrupted spontaneously, and that the crystal structure represents only a snapshot of a complex conformational dynamics. Atomic force microscopy (AFM) studies observed nucleosomal DNA looping (4), and intermediates composed of tetramers and hexamers (5), while conformational changes of the histone octamer inside the nucleosome were recently detected using cryo-electon microscopy (6). Moreover, nucleosomes have been shown to spontaneously unwrap DNA from its ends in a process termed "thermal breathing" (5,(7)(8)(9)(10)(11)(12). The momentary exposure of the DNA was shown to facilitate the invasion of regulatory proteins to nucleosomal DNA (7, 8, 10) and the elongation by RNAP (4, 13), highlighting the potential effect of these dynamics on the process of transcription.Previous studies have indicated the existence of an additional type of thermally driven dynamics: the spontaneous "mobility" or "thermal sliding" of nucleosomes by which their center of mass repositions on the DNA in an unprompted longitudinal-like movement. Initial studies using 2D gel electrophoresis (14,15) reported that nucleosomes are able to reposition over timescales of hours when incubated at 37°C, but not at 4°C. Later experiments used chemically modified H4 histones, capable of inducing a cleavage at the nucleosome's dyad (16), and found that the repositioning rates depend on the positioning sequence and the length of the DNA fragment. Others showed that sin mutations, which weaken the binding ...

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Section: Discussionmentioning

confidence: 99%

The base pair-scale diffusion of nucleosomes modulates binding of transcription factors

Rudnizky

Khamis

Malik

et al. 2019

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

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“…(1) The mechanism through which estradiol rapidly suppresses LH secretion (2) The structure of the GnRH receptor (GnRHR) expressed on the surface of gonadotrophs (3) The existence of other receptors on the surface of gonadotrophs, which regulate LH and FSH secretion. This review discusses mainly rapid (within 30 min) pathways to alter LH and FSH secretion from gonadotrophs [4,5,[8][9][10], without alterations in mRNA expression of the LHα, LHβ, or FSHβ subunits in gonadotrophs. Any mechanism that inhibits the rapid stimulation of LH and FSH by GnRH may potentially function more rapidly (within few minutes), suggesting the importance of unidentified cell membrane receptors rather than nuclear receptors.…”

Section: Introductionmentioning

confidence: 99%

“…This review discusses mainly rapid (within 30 min) pathways to alter LH and FSH secretion from gonadotrophs [ 4 , 5 , 8 , 9 , 10 ], without alterations in mRNA expression of the LHα, LHβ, or FSHβ subunits in gonadotrophs. Any mechanism that inhibits the rapid stimulation of LH and FSH by GnRH may potentially function more rapidly (within few minutes), suggesting the importance of unidentified cell membrane receptors rather than nuclear receptors.…”

Section: Introductionmentioning

confidence: 99%

Discovery of new receptors regulating luteinizing hormone and follicle-stimulating hormone secretion by bovine gonadotrophs to explore a new paradigm for mechanisms regulating reproduction

Kadokawa

2020

J. Reprod. Dev.

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Previous studies in the 1960s and 1970s have reported that both gonadotropin-releasing hormone (GnRH) and estradiol-activated nuclear estrogen receptors regulate gonadotropin secretion in women. However, I had previously reported that gonadotroph function is regulated by complex crosstalk between several membrane receptors. RNA-seq had previously revealed 259 different receptor genes expressed in the anterior pituitary of heifers. However, the biological roles of most of these receptors remain unknown. I identified four new receptors of interest: G protein-coupled receptor 30 (GPR30), anti-Mullerian hormone (AMH) receptor type 2 (AMHR2), and G protein-coupled receptors 61 and 153 (GPR61 and GPR153). GPR30 rapidly (within a few minutes) mediates picomolar, but not nanomolar, levels of estradiol to suppress GnRH-induced luteinizing hormone (LH) secretion from bovine gonadotrophs, without decreasing mRNA expressions of the LHα, LHβ, or follicle-stimulating hormone (FSH) β subunits. GPR30 is activated by other endogenous estrogens, estrone and estriol. Moreover, GPR30 activation by zearalenone, a nonsteroidal mycoestrogen, suppresses LH secretion. AMHR2, activated by AMH, stimulates LH and FSH secretion, thus regulating gonadotrophs, where other TGF-β family members, including inhibin and activin, potentially affect FSH secretion. I also show that GPR61, activated by its ligand (recently discovered) significantly alters LH and FSH secretion. GPR61, GPR153, and AMHR2 colocalize with the GnRH receptor in unevenly dispersed areas of the bovine gonadotroph cell surface, probably lipid rafts. The findings summarized in this review reveal a new paradigm regarding the mechanisms regulating reproduction via novel receptors expressed on bovine gonadotrophs.

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“…into altered patterns of gene expression, which can have a profound and long-term effect on the phenotype. The epigenome undergoes considerable modification during various stages of development and, as is becoming clear, plays a role in the maturation of the reproductive axis at puberty as well as adult reproductive function [14][15][16] . We therefore hypothesized that the early-life environment programs reproductive strategies through epigenetic-driven mechanisms.…”

Section: Epigenetic Modification Provides a Means Of Sensing The Envimentioning

confidence: 99%

Early-life environment programs reproductive strategies through epigenetic regulation ofSRD5A1

Bar-Sadeh

Eden

Pnueli

et al. 2020

Preprint

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Reproductive function and duration of the reproductive life span are phenotypically plastic and programmed in response to the early-life environment. Such adaptive responses are described and rationalized in life history theory in the context of resource availability, but the molecular mechanisms responsible have remained enigmatic. In this study, we hypothesized that epigenetic modifications underlie adaptive reproductive strategies, and found distinct methylation patterns in buccal DNA of Bangladeshi women who grew up in Bangladesh or the UK. The later pubertal onset and lower ovarian reserve associated with Bangladeshi childhood was seen to correlate with more numerous childhood infections, so we adopted a mouse model of pre-pubertal colitis to mimic these conditions. These mice have a similarly-altered reproductive phenotype, which enabled us to determine its mechanistic basis. Several genes encoding proteins with known functions in follicle recruitment were differentially expressed in the mice ovaries, and were also differentially methylated in the women’s buccal DNA. One of these, SRD5A1 which encodes the steroidogenic enzyme 5α reductase-1, was down-regulated in the mice ovaries and hyper methylated at the same putative transcriptional enhancer as in the women’s DNA; the levels of methylation correlating with gene expression levels. Srd5a1 expression was down-regulated also in the hypothalamus where 5α reductase-1 catalyzes production of neurosteroids that regulate gonadotropin releasing hormone (GnRH). Chemical inhibition of this enzyme affected both GnRH synthesis and release, and resulted in delayed pubertal onset in vivo. The activity of 5α reductase-1 in hypothalamus and ovary and the sensitivity of SRD5A1 to epigenetic regulation attest to its role in directing long-term physiological strategies in response to environmental conditions. In the reproductive axis, this includes timing of pubertal onset, adult reproductive function and duration of the reproductive lifespan.

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Multifaceted Targeting of the Chromatin Mediates Gonadotropin-Releasing Hormone Effects on Gene Expression in the Gonadotrope

Cited by 25 publications

References 97 publications

The base pair-scale diffusion of nucleosomes modulates binding of transcription factors

The base pair-scale diffusion of nucleosomes modulates binding of transcription factors

Discovery of new receptors regulating luteinizing hormone and follicle-stimulating hormone secretion by bovine gonadotrophs to explore a new paradigm for mechanisms regulating reproduction

Early-life environment programs reproductive strategies through epigenetic regulation ofSRD5A1

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