Delta Notch and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors

Abstract

Hes and Hey genes are the mammalian counterparts of the Hairy and Enhancer-of-split type of genes in Drosophila and they represent the primary targets of the Delta–Notch signaling pathway. Hairy-related factors control multiple steps of embryonic development and misregulation is associated with various defects. Hes and Hey genes (also called Hesr, Chf, Hrt, Herp or gridlock) encode transcriptional regulators of the basic helix-loop-helix class that mainly act as repressors. The molecular details of how Hes and Hey proteins control transcription are still poorly understood, however.Proposed modes of action include direct binding to N- or E-box DNA sequences of target promoters as well as indirect binding through other sequence-specific transcription factors or sequestration of transcriptional activators. Repression may rely on recruitment of corepressors and induction of histone modifications, or even interference with the general transcriptional machinery. All of these models require extensive protein–protein interactions. Here we review data published on protein–protein and protein–DNA interactions of Hairy-related factors and discuss their implications for transcriptional regulation. In addition, we summarize recent progress on the identification of potential target genes and the analysis of mouse models.

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

“…However hepatic transcription of another Notch target, the transcription factor Hes1 , which has been implicated in the regulation of hepatic lipid metabolism and fatty liver disease (FLD), was unchanged (data not shown) [41]. The levels of mRNAs encoding the Hes1 related genes Hes5 , Hey1 and Hey2 were also unchanged by ICD-E expression, as were Sox9 and Hnf1β (data not shown) [22], [42]. In contrast to the liver, strong induction of Hes5 follows expression of ICD-E in the intestine [20].…”

The Notch signaling pathway: Transcriptional regulation at Notch target genes

“…The hairy/enhancer of split (Hes) genes are highly conserved proteins that are regulated by Notch in multiple cell types, reviewed in [7,8]. Hairy/Enhancer of split family genes were first described as neurogenic genes in Drosophila (like Notch, Deltex and Mastermind), since embryos lacking the function of these genes showed an increased number of neuroblasts at the expense of epidermal precursors, reviewed in [2,9].…”

“…Several lines of evidence have suggested that these genes are indeed direct Notch target genes: a) The promoters of Hes1, Hes5 and Hes7 as well as Hey1, Hey2 and HeyL (subfamily of Hes, related with YRPW motif) can be activated by a constitutive active form of Notch1 [10 -12], reviewed in [7]; constitutive active Notch describes a mutant of Notch that is continuously proteolytically processed and migrating to the nucleus, b) endogenous Hey1 and Hey2 show an upregulation by NICD in several different cell lines [13], c) in co-culture experiments with Notch-ligand expressing cells, that achieve a more physiological level of Notch signaling, these genes are upregulated as well [13 -15]; these experiments were also performed in the presence of cyclohexamide, an inhibitor of protein synthesis, to exclude secondary effects, d) k-secretase inhibitor DAPT, which prevents cleavage of Notch, was added to Tcell leukemia cell lines which show constitutive-active Notch signaling; subsequent microarray analysis identified again members of this transcription factor family as direct Notch target genes [16]. Therefore, in mammals, the best-described Notch target genes are indeed the transcription factors Hes1, Hes5 and Hey1 [8,17]. Hes and Hey proteins are helix-loop-helix transcription factors that function as transcriptional repressors.…”

Expression Dynamics and Functions of Hes Factors in Development and Diseases

“…The WRPW domain, located at the C-terminal end, is essential for the repressor activity via recruitment of the co-repressor Transducin-like E(spl) (TLE1-4)/ Groucho-related gene (Grg), a homologue of Drosophila Groucho. The Hey family factors contain a YRPW (Tyr-Arg-Pro-Trp) motif instead of the WRPW motif, which contributes to the weaker binding of Hey factors to TLE than the Hes factors (Iso et al, 2001;Fischer & Gessler, 2007).…”