The Groucho/Transducin-like Enhancer of split Transcriptional Repressors Interact with the Genetically Defined Amino-terminal Silencing Domain of Histone H3

The transcriptional repressor Hes1, a basic helix-loop-helix family protein, periodically changes its expression in the presomitic mesoderm. Its periodic pattern of expression is retained in a number of cultured murine cell lines. In this paper, we introduce an extended mathematical model for Hes1 oscillatory expression that includes regulation of Hes1 transcription by Drosophila Groucho (Gro) or its vertebrate counterpart, the transducine-like enhancer of split/Groucho-related gene product 1 (TLE1). Gro/TLE1 is a necessary corepressor required by a number of DNA-binding transcriptional repressors, including Hes1. Models of direct repression via Hes1 typically display an expression overshoot after transcription initiation which is not seen in the experimental data. However, numerical simulation and theoretical predictions of our model show that the cofactor Gro/TLE1 reduces the overshoot and is thus necessary for a rapid and finely tuned response of Hes1 to activation signals. Further, from detailed linear stability and numerical bifurcation analysis and simulations, we conclude that the cooperativity coefficient ( h ) for Hes1 self-repression should be large (i.e. h ≥4). Finally, we introduce the characteristic turnaround duration, and show that for our model the duration of the repression loop is between 40 and 60 min.

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Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning

Oncogene ◽

10.1038/sj.onc.1205094 ◽

2001 ◽

Vol 20 (58) ◽

pp. 8342-8357 ◽

Cited By ~ 255

Author(s):

Robert L Davis ◽

David L Turner

Keyword(s):

Cellular Differentiation ◽

Transcriptional Repressors ◽

Embryonic Patterning ◽

Related Proteins ◽

Enhancer Of Split

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Structural basis for recognition of diverse transcriptional repressors by the TOPLESS family of corepressors

Science Advances ◽

10.1126/sciadv.1500107 ◽

2015 ◽

Vol 1 (6) ◽

pp. e1500107 ◽

Cited By ~ 59

Author(s):

Jiyuan Ke ◽

Honglei Ma ◽

Xin Gu ◽

Adam Thelen ◽

Joseph S. Brunzelle ◽

...

Keyword(s):

Stress Responses ◽

Structural Basis ◽

General Mechanism ◽

Auxin Signaling ◽

Ethylene Response Factor ◽

Large Set ◽

Transcriptional Repressors ◽

Sequence Alignments ◽

Amino Terminal ◽

Transcriptional Corepressors

TOPLESS (TPL) and TOPLESS-related (TPR) proteins comprise a conserved family of plant transcriptional corepressors that are related to Tup1, Groucho, and TLE (transducin-like enhancer of split) corepressors in yeast, insects, and mammals. In plants, TPL/TPR corepressors regulate development, stress responses, and hormone signaling through interaction with small ethylene response factor–associated amphiphilic repression (EAR) motifs found in diverse transcriptional repressors. How EAR motifs can interact with TPL/TPR proteins is unknown. We confirm the amino-terminal domain of the TPL family of corepressors, which we term TOPLESS domain (TPD), as the EAR motif–binding domain. To understand the structural basis of this interaction, we determined the crystal structures of the TPD of rice (Os) TPR2 in apo (apo protein) state and in complexes with the EAR motifs from Arabidopsis NINJA (novel interactor of JAZ), IAA1 (auxin-responsive protein 1), and IAA10, key transcriptional repressors involved in jasmonate and auxin signaling. The OsTPR2 TPD adopts a new fold of nine helices, followed by a zinc finger, which are arranged into a disc-like tetramer. The EAR motifs in the three different complexes adopt a similar extended conformation with the hydrophobic residues fitting into the same surface groove of each OsTPR2 monomer. Sequence alignments and structure-based mutagenesis indicate that this mode of corepressor binding is highly conserved in a large set of transcriptional repressors, thus providing a general mechanism for gene repression mediated by the TPL family of corepressors.

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MP41-08 AMINO-TERMINAL ENHANCER OF SPLIT/ AES IS A TUMOR AND METASTASIS SUPPRESSOR OF PROSTATE CANCER

The Journal of Urology ◽

10.1016/j.juro.2014.02.1225 ◽

2014 ◽

Vol 191 (4S) ◽

Author(s):

Yoshiyuki Okada ◽

Fumihiko Kakizaki ◽

Masayuki Uegaki ◽

Takayuki Goto ◽

Takeshi Yoshikawa ◽

...

Keyword(s):

Prostate Cancer ◽

Metastasis Suppressor ◽

Amino Terminal ◽

Enhancer Of Split

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Inhibition of Nuclear Factor-κB-mediated Transcription by Association with the Amino-terminal Enhancer of Split, a Groucho-related Protein Lacking WD40 Repeats

Journal of Biological Chemistry ◽

10.1074/jbc.275.6.4383 ◽

2000 ◽

Vol 275 (6) ◽

pp. 4383-4390 ◽

Cited By ~ 71

Author(s):

Toshifumi Tetsuka ◽

Hiroaki Uranishi ◽

Hiroto Imai ◽

Takao Ono ◽

Shin-ichi Sonta ◽

...

Keyword(s):

Nuclear Factor Κb ◽

Nuclear Factor ◽

Related Protein ◽

Amino Terminal ◽

Enhancer Of Split ◽

Wd40 Repeats

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Methylation of Histone H3 Lysine 36 Is Required for Normal Development in Neurospora crassa

Eukaryotic Cell ◽

10.1128/ec.4.8.1455-1464.2005 ◽

2005 ◽

Vol 4 (8) ◽

pp. 1455-1464 ◽

Cited By ~ 59

Author(s):

Keyur K. Adhvaryu ◽

Stephanie A. Morris ◽

Brian D. Strahl ◽

Eric U. Selker

Keyword(s):

Neurospora Crassa ◽

Growth And Development ◽

Histone H3 ◽

Normal Growth ◽

Wild Type ◽

Set Domain ◽

Amino Terminal ◽

Histone H3 Gene ◽

Type Gene

ABSTRACT The SET domain is an evolutionarily conserved domain found predominantly in histone methyltransferases (HMTs). The Neurospora crassa genome includes nine SET domain genes (set-1 through set-9) in addition to dim-5, which encodes a histone H3 lysine 9 HMT required for DNA methylation. We demonstrate that Neurospora set-2 encodes a histone H3 lysine 36 (K36) methyltransferase and that it is essential for normal growth and development. We used repeat induced point mutation to make a set-2 mutant (set-2 RIP1 ) with multiple nonsense mutations. Western analyses revealed that the mutant lacks SET-2 protein and K36 methylation. An amino-terminal fragment that includes the AWS, SET, and post-SET domains of SET-2 proved sufficient for K36 HMT activity in vitro. Nucleosomes were better substrates than free histones. The set-2 RIP1 mutant grows slowly, conidiates poorly, and is female sterile. Introducing the wild-type gene into the mutant complemented the defects, confirming that they resulted from loss of set-2 function. We replaced the wild-type histone H3 gene (hH3) with an allele producing a Lys to Leu substitution at position 36 and found that this hH3 K36L mutant phenocopied the set-2 RIP1 mutant, confirming that the observed defects in growth and development result from inability to methylate K36 of H3. Finally, we used chromatin immunoprecipitation to demonstrate that actively transcribed genes in Neurospora crassa are enriched for H3 methylated at lysines 4 and 36. Taken together, our results suggest that methylation of K36 in Neurospora crassa is essential for normal growth and development.

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Inhibition of Androgen Receptor-Mediated Transcription by Amino-Terminal Enhancer of split

Molecular and Cellular Biology ◽

10.1128/mcb.21.14.4614-4625.2001 ◽

2001 ◽

Vol 21 (14) ◽

pp. 4614-4625 ◽

Cited By ~ 73

Author(s):

Xin Yu ◽

Peng Li ◽

Robert G. Roeder ◽

Zhengxin Wang

Keyword(s):

Androgen Receptor ◽

Nuclear Extract ◽

Basal Transcription ◽

Hela Nuclear Extract ◽

Protein Protein Interaction ◽

Transcription System ◽

Amino Terminal ◽

Two Hybrid ◽

Enhancer Of Split

ABSTRACT A yeast two-hybrid assay has identified an androgen-dependent interaction of androgen receptor (AR) with amino-terminal enhancer of split (AES), a member of the highly conserved Groucho/TLE family of corepressors. Full-length AR, as well as the N-terminal fragment of AR, showed direct interactions with AES in in vitro protein-protein interaction assays. AES specifically inhibited AR-mediated transcription in a well-defined cell-free transcription system and interacted specifically with the basal transcription factor (TFIIE) in HeLa nuclear extract. These observations implicate AES as a selective repressor of ligand-dependent AR-mediated transcription that acts by directly interacting with AR and by targeting the basal transcription machinery.

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The Yng1p Plant Homeodomain Finger Is a Methyl-Histone Binding Module That Recognizes Lysine 4-Methylated Histone H3

Molecular and Cellular Biology ◽

10.1128/mcb.00573-06 ◽

2006 ◽

Vol 26 (21) ◽

pp. 7871-7879 ◽

Cited By ~ 114

Author(s):

David G. E. Martin ◽

Kristin Baetz ◽

Xiaobing Shi ◽

Kay L. Walter ◽

Vicki E. MacDonald ◽

...

Keyword(s):

Histone H3 ◽

General Role ◽

Histone Binding ◽

Phd Finger ◽

Amino Terminal ◽

Plant Homeodomain Finger ◽

Plant Homeodomain ◽

Insight Into

ABSTRACT The ING (inhibitor of growth) protein family includes a group of homologous nuclear proteins that share a highly conserved plant homeodomain (PHD) finger domain at their carboxyl termini. Members of this family are found in multiprotein complexes that posttranslationally modify histones, suggesting that these proteins serve a general role in permitting various enzymatic activities to interact with nucleosomes. There are three members of the ING family in Saccharomyces cerevisiae: Yng1p, Yng2p, and Pho23p. Yng1p is a component of the NuA3 histone acetyltransferase complex and is required for the interaction of NuA3 with chromatin. To gain insight into the function of the ING proteins, we made use of a genetic strategy to identify genes required for the binding of Yng1p to histones. Using the toxicity of YNG1 overexpression as a tool, we showed that Yng1p interacts with the amino-terminal tail of histone H3 and that this interaction can be disrupted by loss of lysine 4 methylation within this tail. Additionally, we mapped the region of Yng1p required for overexpression of toxicity to the PHD finger, showed that this region capable of binding lysine 4-methylated histone H3 in vitro, and demonstrated that mutations of the PHD finger that abolish binding in vitro are no longer toxic in vivo. These results identify a novel function for the Yng1p PHD finger in promoting stabilization of the NuA3 complex at chromatin through recognition of histone H3 lysine 4 methylation.

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