Paradox of sonic hedgehog (SHH) transcriptional regulation: Alternative transcription initiation overrides the effect of downstream promoter DNA methylation

Haaf, Anette ten; Franken, Laura; Heymann, Caroline; Serenyi, Sonja von; Cornélissen, Christian; Hoon, Joep P.J. de; Veeck, Jürgen; Lüscher, Bernhard; Knüchel, Ruth; Dahl, Edgar

doi:10.4161/epi.6.4.14952

Cited by 10 publications

(3 citation statements)

References 40 publications

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“…The dominant role of histone modifications is further underscored by the fact that monocytes show high levels of DNA methylation. Although DNA methylation is usually interpreted as a repressive chromatin mark, this study as well as a number of recent other studies show that DNA methylation in the absence of repressive histone marks permits active gene transcription [38, 50–55]. This is also in line with previous studies showing that the presence of the 3MeK27H3 histone modification correlated with lack of transcription despite the absence of DNA methylation [51, 56, 57].…”

Section: Discussionsupporting

confidence: 90%

Epigenetic control of CCR5 transcript levels in immune cells and modulation by small molecules inhibitors

Wierda

Kuipers

Eggermond

et al. 2012

J Cellular Molecular Medi

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Previously, we have shown that CCR5 transcription is regulated by CREB-1. However, the ubiquitous pattern of CREB-1 expression suggests the involvement of an additional level of transcriptional control in the cell type-specific expression of CCR5. In this study we show that epigenetic changes (i.e. DNA methylation and histone modifications) within the context of the CCR5 P1 promoter region correlate with transcript levels of CCR5 in healthy and in malignant CD4+ T lymphocytes as well as in CD14+ monocytes. In normal naïve T cells and CD14+ monocytes the CCR5 P1 promoter resembles a bivalent chromatin state, with both repressive and permissive histone methylation and acetylation marks. The CCR5 expressing CD14+ monocytes however show much higher levels of acetylated histone H3 (AcH3) compared to the non–CCR5-expressing naïve T cells. Combined with a highly methylated promoter in CD14+ monocytes, this indicates a dominant role for AcH3 in CCR5 transcription. We also show that pharmacological interference in the epigenetic repressive mechanisms that account for the lack of CCR5 transcription in T leukemic cell lines results in an increase in CREB-1 association with CCR5 P1 chromatin. Furthermore RNA polymerase II was also recruited into CCR5 P1 chromatin resulting in CCR5 re-expression. Together, these data indicate that epigenetic modifications of DNA, and of histones, contribute to the control of CCR5 transcription in immune effector cells.

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Section: Discussionsupporting

confidence: 90%

Epigenetic control of CCR5 transcript levels in immune cells and modulation by small molecules inhibitors

Wierda

Kuipers

Eggermond

et al. 2012

J Cellular Molecular Medi

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“…SHH promoter region hypomethylation is frequently observed in breast carcinomas and is significantly associated with SHH up-regulation [58,59]. SHH gene transcription may not be solely dependent on promoter demethylation but could also be regulated by transcription factors [60]. A positive correlation between the expression of the transcription factor NF-κB and SHH up-regulation was observed in breast clinical samples [59].…”

Section: Role Of Hedgehog Signalling Pathway In Breast Carcinogenesismentioning

confidence: 99%

The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy

et al. 2013

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Despite the progress achieved in breast cancer screening and therapeutic innovations, the basal-like subtype of breast cancer (BLBC) still represents a particular clinical challenge. In order to make an impact on survival in this type of aggressive breast cancer, new targeted therapeutic agents are urgently needed. Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent approval of vismodegib, an orally bioavailable small-molecule inhibitor of Smoothened, validates Hh signalling as a valuable therapeutic target. A number of recent publications have highlighted a role for Hh signalling in breast cancer models and clinical specimens. Interestingly, Hh ligand overexpression is associated with the BLBC phenotype and a poor outcome in terms of metastasis and breast cancer-related death. In this review, we provide a comprehensive overview of the canonical Hh signalling pathway in mammals, highlight its roles in mammary gland development and breast carcinogenesis and discuss its potential therapeutic value in BLBC.

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“…From there, transcription of three members of the glioblastoma (Gli) family (Gli1, Gli2, Gli3) is triggered [ 176 , 177 ]. Shh has two different transcription start sites (TSS), and DNA methylation of these TSS and alternative promoter usage act as transcriptional regulators of Shh expression [ 178 , 179 ]. Laporta et al were the first to describe the role of serotonin in switching TSS in the Shh promoter region to regulate PTHrP expression during lactation, further highlighting the importance of serotonin during lactation [ 173 ].…”

Section: Calcium and Bone Metabolismmentioning

confidence: 99%

The Serotonergic System and Bone Metabolism During Pregnancy and Lactation and the Implications of SSRI Use on the Maternal-Offspring Dyad

Fricke

Hernández

2023

J Mammary Gland Biol Neoplasia

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Lactation is a physiological adaptation of the class Mammalia and is a product of over 200 million years of evolution. During lactation, the mammary gland orchestrates bone metabolism via serotonin signaling in order to provide sufficient calcium for the offspring in milk. The role of serotonin in bone remodeling was first discovered over two decades ago, and the interplay between serotonin, lactation, and bone metabolism has been explored in the years following. It is estimated that postpartum depression affects 10–15% of the population, and selective serotonin reuptake inhibitors (SSRI) are often used as the first-line treatment. Studies conducted in humans, nonhuman primates, sheep, and rodents have provided evidence that there are consequences on both parent and offspring when serotonin signaling is disrupted during the peripartal period; however, the long-term consequences of disruption of serotonin signaling via SSRIs during the peripartal period on the maternal and offspring skeleton are not fully known. This review will focus on the relationship between the mammary gland, serotonin, and bone remodeling during the peripartal period and the skeletal consequences of the dysregulation of the serotonergic system in both human and animal studies.

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Paradox of sonic hedgehog (SHH) transcriptional regulation: Alternative transcription initiation overrides the effect of downstream promoter DNA methylation

Cited by 10 publications

References 40 publications

Epigenetic control of CCR5 transcript levels in immune cells and modulation by small molecules inhibitors

Epigenetic control of CCR5 transcript levels in immune cells and modulation by small molecules inhibitors

The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy

The Serotonergic System and Bone Metabolism During Pregnancy and Lactation and the Implications of SSRI Use on the Maternal-Offspring Dyad

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