Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The essential role of acetyllysine binding by the YEATS domain in transcriptional regulation.

ABSTRACT: The YEATS domains of AF9 and Taf14 have recently been found to recognize the histone H3K9ac modification. In this commentary, we discuss the mechanistic and biological implications of this interaction. We compare structures of the YEATS-H3K9ac complexes the highlighting a novel mechanism for the acetyllysine recognition through the aromatic cage. We also summarize the latest findings underscoring a critical role of the acetyllysine binding function of AF9 and Taf14 in transcriptional regulation and DNA repair.

SUBMITTER: Andrews FH

PROVIDER: S-EPMC4802754 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The essential role of acetyllysine binding by the YEATS domain in transcriptional regulation.

Andrews Forest H FH Shanle Erin K EK Strahl Brian D BD Kutateladze Tatiana G TG

Transcription 20160101 1

The YEATS domains of AF9 and Taf14 have recently been found to recognize the histone H3K9ac modification. In this commentary, we discuss the mechanistic and biological implications of this interaction. We compare structures of the YEATS-H3K9ac complexes the highlighting a novel mechanism for the acetyllysine recognition through the aromatic cage. We also summarize the latest findings underscoring a critical role of the acetyllysine binding function of AF9 and Taf14 in transcriptional regulation ...[more]

PMID: 26934307

Similar Datasets

Regulation of transcriptional activators by DNA-binding domain ubiquitination.

Project description:Ubiquitin is a key component of the regulatory network that maintains gene expression in eukaryotes, yet the molecular mechanism(s) by which non-degradative ubiquitination modulates transcriptional activator (TA) function is unknown. Here endogenous p53, a stress-activated transcription factor required to maintain health, is stably monoubiquitinated, following pathway activation by IR or Nutlin-3 and localized to the nucleus where it becomes tightly associated with chromatin. Comparative structure-function analysis and in silico modelling demonstrate a direct role for DNA-binding domain (DBD) monoubiquitination in TA activation. When attached to the DBD of either p53, or a second TA IRF-1, ubiquitin is orientated towards, and makes contact with, the DNA. The contact is made between a predominantly cationic surface on ubiquitin and the anionic DNA. Our data demonstrate an unexpected role for ubiquitin in the mechanism of TA-activity enhancement and provides insight into a new level of transcriptional regulation.

| S-EPMC5423116 | biostudies-literature

Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer.

Project description:Growing evidence suggests prevalence of transcriptional condensates on chromatin, yet their mechanisms of formation and functional significance remain largely unclear. In human cancer, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation ability. Here, we show that these mutations, clustered in ENL's structured acetyl-reading YEATS domain, trigger aberrant condensates at native genomic targets through multivalent homotypic and heterotypic interactions. Mechanistically, mutation-induced structural changes in the YEATS domain, ENL's two disordered regions of opposing charges, and the incorporation of extrinsic elongation factors are all required for ENL condensate formation. Extensive mutagenesis establishes condensate formation as a driver of oncogenic gene activation. Furthermore, expression of ENL mutants beyond the endogenous level leads to non-functional condensates. Our findings provide new mechanistic and functional insights into cancer-associated condensates and support condensate dysregulation as an oncogenic mechanism.

| S-EPMC10071517 | biostudies-literature

Structural insights into the ?-?-? stacking mechanism and DNA-binding activity of the YEATS domain.

Project description:The YEATS domain has been identified as a reader of histone acylation and more recently emerged as a promising anti-cancer therapeutic target. Here, we detail the structural mechanisms for ?-?-? stacking involving the YEATS domains of yeast Taf14 and human AF9 and acylated histone H3 peptides and explore DNA-binding activities of these domains. Taf14-YEATS selects for crotonyllysine, forming ? stacking with both the crotonyl amide and the alkene moiety, whereas AF9-YEATS exhibits comparable affinities to saturated and unsaturated acyllysines, engaging them through ? stacking with the acyl amide. Importantly, AF9-YEATS is capable of binding to DNA, whereas Taf14-YEATS is not. Using a structure-guided approach, we engineered a mutant of Taf14-YEATS that engages crotonyllysine through the aromatic-aliphatic-aromatic ? stacking and shows high selectivity for the crotonyl H3K9 modification. Our findings shed light on the molecular principles underlying recognition of acyllysine marks and reveal a previously unidentified DNA-binding activity of AF9-YEATS.

| S-EPMC6212594 | biostudies-literature

An unexpected role for Dicer as a reader of the unacetylated DNA binding domain of p53 in transcriptional regulation

Project description:Description Dicer acts as an unexpected cofactor in modulating promoter-specific regulation of p53 targets in an acetylation-dependent manner. Here, we identified Dicer as a major cellular factor that recognizes the DNA binding domain (DBD) of p53 in a manner dependent on its acetylation status. Upon binding the unacetylated DBD, Dicer is recruited to the promoters of p53 target genes, where it represses p53-mediated transcriptional activation. Conversely, knockdown or knockout of endogenous Dicer leads to up-regulation of p53-mediated transcriptional activation without increasing its protein levels. Moreover, Dicer-mediated repression is independent of its intrinsic endoribonuclease activity; instead, Dicer directly represses transcription by recruiting the SUV39H1 histone methyltransferase. However, upon DNA damage, Dicer-mediated repression is abrogated by stress-induced acetylation at the DBD of p53. Notably, the inability of acetylation-defective p53-3KR in transcription is partially but significantly restored upon loss of Dicer expression. Our study reveals that Dicer acts as an unexpected acetylation “reader” for p53 and thus has important implications regarding the mechanism of acetylation-mediated regulation of p53 transcriptional program.

| S-EPMC8550248 | biostudies-literature

Fragment-Based Discovery of AF9 YEATS Domain Inhibitors.

Project description:YEATS (YAF9, ENL, AF9, TAF14, SAS5) family proteins recognize acylated histones and in turn regulate chromatin structure, gene transcription, and stress signaling. The chromosomal translocations of ENL and mixed lineage leukemia are considered oncogenic drivers in acute myeloid leukemia and acute lymphoid leukemia. However, known ENL YEATS domain inhibitors have failed to suppress the proliferation of 60 tested cancer cell lines. Herein, we identified four hits from the NMR fragment-based screening against the AF9 YEATS domain. Ten inhibitors of new chemotypes were then designed and synthesized guided by two complex structures and affinity assays. The complex structures revealed that these inhibitors formed an extra hydrogen bond to AF9, with respect to known ENL inhibitors. Furthermore, these inhibitors demonstrated antiproliferation activities in AF9-sensitive HGC-27 cells, which recapitulated the phenotype of the CRISPR studies against AF9. Our work will provide the basis for further structured-based optimization and reignite the campaign for potent AF9 YEATS inhibitors as a precise treatment for AF9-sensitive cancers.

| S-EPMC8998803 | biostudies-literature

Asf1-like structure of the conserved Yaf9 YEATS domain and role in H2A.Z deposition and acetylation.

Project description:Chromatin can be modified by posttranslational modifications of histones, ATP-dependent remodeling, and incorporation of histone variants. The Saccharomyces cerevisiae protein Yaf9 is a subunit of both the essential histone acetyltransferase complex NuA4 and the ATP-dependent chromatin remodeling complex SWR1-C, which deposits histone variant H2A.Z into euchromatin. Yaf9 contains a YEATS domain, found in proteins associated with multiple chromatin-modifying enzymes and transcription complexes across eukaryotes. Here, we established the conservation of YEATS domain function from yeast to human, and determined the structure of this region from Yaf9 by x-ray crystallography to 2.3 A resolution. The Yaf9 YEATS domain consisted of a beta-sandwich characteristic of the Ig fold and contained three distinct conserved structural features. The structure of the Yaf9 YEATS domain was highly similar to that of the histone chaperone Asf1, a similarity that extended to an ability of Yaf9 to bind histones H3 and H4 in vitro. Using structure-function analysis, we found that the YEATS domain was required for Yaf9 function, histone variant H2A.Z chromatin deposition at specific promoters, and H2A.Z acetylation.

| S-EPMC2799888 | biostudies-literature

Cell-Based Ligand Discovery for the ENL YEATS Domain.

Project description:ENL is a transcriptional coactivator that recruits elongation machinery to active cis-regulatory elements upon binding of its YEATS domain-a chromatin reader module-to acylated lysine side chains. Discovery chemistry for the ENL YEATS domain is highly motivated by its significance in acute leukemia pathophysiology, but cell-based assays able to support large-scale screening or hit validation efforts do not presently exist. Here, we report on the discovery of a target engagement assay that allows for high-throughput ligand discovery in living cells. This assay is based on the cellular thermal shift assay (CETSA) but does not require exposing cells to elevated temperatures, as small-molecule ligands are able to stabilize the ENL YEATS domain at 37 °C. By eliminating temperature shifts, we developed a simplified target engagement assay that requires just two steps: drug treatment and luminescence detection. To demonstrate its value for higher throughput applications, we miniaturized the assay to a 1536-well format and screened 37 120 small molecules, ultimately identifying an acyl-lysine-competitive ENL/AF9 YEATS domain inhibitor.

| S-EPMC7384521 | biostudies-literature

Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

Project description:YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.

| S-EPMC6348381 | biostudies-literature

Development of potent dimeric inhibitors of GAS41 YEATS domain.

Project description:GAS41 is an emerging oncogene overexpressed and implicated in multiple cancers, including non-small cell lung cancer (NSCLC). GAS41 is a dimeric protein that contains the YEATS domain, which is involved in the recognition of lysine-acylated histones. Here, we report the development of GAS41 YEATS inhibitors by employing a fragment-based screening approach. These inhibitors bind to GAS41 YEATS domain in a channel constituting a recognition site for acylated lysine on histone proteins. To enhance inhibitory activity, we developed a dimeric analog with nanomolar activity that blocks interactions of GAS41 with acetylated histone H3. Our lead compound engages GAS41 in cells, blocks proliferation of NSCLC cells, and modulates expression of GAS41-dependent genes, validating on-target mechanism of action. This study demonstrates that disruption of GAS41 protein-protein interactions may represent an attractive approach to target lung cancer cells. This work exemplifies the use of bivalent inhibitors as a general strategy to block challenging protein-protein interactions.

| S-EPMC8923076 | biostudies-literature

Essential role of Ahnak in adipocyte differentiation leading to the transcriptional regulation of Bmpr1? expression.

Project description:The role of Ahnak in obesity has been reported previously. Loss of Ahnak leads to decreased Bmp4/Smad1 signaling, resulting in the downregulation of adipocyte differentiation. However, the biological significance of Ahnak remains largely unknown. In this study, we demonstrate that Ahnak-mediated impaired adipogenesis results in decreased Bmpr1? transcriptional expression. To confirm this, Ahnak siRNA was used to knock-down Ahnak in C3H10T1/2 and primary stromal vascular fraction cells. Ahnak siRNA transfected cells showed suppression of Bmpr1? expression and decreased BMP4/ Bmpr1? signaling. The differential adipogenesis was further confirmed by knock-down of Bmpr1? in C3H10T1/2 cells, which resulted in reduced adipogenesis. Moreover, stable Ahnak knock-out C3H10T1/2 cells stably transfected with Ahnak CRISPR/Cas9 plasmid suppressed expression of Bmpr1? and prevented differentiation into adipocytes. Furthermore, we developed immortalized pre-adipocytes from wild-type or Ahnak Knock-out mice's stromal vascular fraction (SVF) to confirm the function of Ahnak in pre-adipocyte transition. Immortalized Ahnak knock-out SVF cells showed lower level of Bmpr1? expression, evidence by their impaired BMP4/Bmpr1? signaling. Upon adipogenic induction, immortalized Ahnak knock-out SVF cells exhibited a marked decrease in adipocyte differentiation compared with immortalized wild-type pre-adipocytes. Furthermore, over-expression of Bmpr1? restored the adipogenic activity of Ahnak knock-out C3H10T1/2 cells and immortalized Ahnak knock-out SVF cells. Our data reveal the missing link in Ahnak-mediated adipose tissue remodeling and suggest that precise regulation of Ahnak in adipose tissue might have a therapeutic advantage for metabolic disease treatment.

| S-EPMC6113281 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data