Class I histone deacetylases (HDAC1, HDAC2, and HDAC3) are recruited by cognate corepressor proteins into specific transcriptional repression complexes that target HDAC activity to chromatin ...resulting in chromatin condensation and transcriptional silencing. We previously reported the structure of HDAC3 in complex with the SMRT corepressor. This structure revealed the presence of inositol-tetraphosphate Ins(1,4,5,6)P4 at the interface of the two proteins. It was previously unclear whether the role of Ins(1,4,5,6)P4 is to act as a structural cofactor or a regulator of HDAC3 activity. Here we report the structure of HDAC1 in complex with MTA1 from the NuRD complex. The ELM2-SANT domains from MTA1 wrap completely around HDAC1 occupying both sides of the active site such that the adjacent BAH domain is ideally positioned to recruit nucleosomes to the active site of the enzyme. Functional assays of both the HDAC1 and HDAC3 complexes reveal that Ins(1,4,5,6)P4 is a bona fide conserved regulator of class I HDAC complexes.
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•Inositol phosphates are bona fide regulators of class I HDAC corepressor complexes•The ELM2-SANT motif is a conserved HDAC corepressor assembly module•MTA1 is a dimer that recruits two HDACs into the NuRD complex•The MTA1-BAH domain is positioned to recruit chromatin to the HDAC active site
Stem cells regenerate tissues in homeostasis and under stress. By taking cues from their microenvironment or “niche,” they smoothly transition between these states. Immune cells have surfaced as ...prominent members of stem cell niches across the body. Here, we draw parallels between different stem cell niches to explore the context-specific interactions that stem cells have with tissue-resident and recruited immune cells. We also highlight stem cells’ innate ability to sense and respond to stress and the enduring memory that forms from such encounters. This fascinating crosstalk holds great promise for novel therapies in inflammatory diseases and regenerative medicine.
Understanding the crosstalk between immune and stem cells under homeostatic conditions provides insights into our understanding of inflammatory disease.
Enhancer elements are genomic regulatory sequences that direct the selective expression of genes so that genetically identical cells can differentiate and acquire the highly specialized forms and ...functions required to build a functioning animal. To differentiate, cells must select from among the ∼106 enhancers encoded in the genome the thousands of enhancers that drive the gene programs that impart their distinct features. We used a genetic approach to identify transcription factors (TFs) required for enhancer selection in fibroblasts. This revealed that the broadly expressed, growth-factor-inducible TFs FOS/JUN (AP-1) play a central role in enhancer selection. FOS/JUN selects enhancers together with cell-type-specific TFs by collaboratively binding to nucleosomal enhancers and recruiting the SWI/SNF (BAF) chromatin remodeling complex to establish accessible chromatin. These experiments demonstrate how environmental signals acting via FOS/JUN and BAF coordinate with cell-type-specific TFs to select enhancer repertoires that enable differentiation during development.
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•Screen for TFs required for enhancer selection using divergent mouse strains•AP-1 TFs (FOS/JUN) are broadly required for enhancer selection in fibroblasts•AP-1 TFs collaborate with cell-type-specific TFs to select enhancers•AP-1 TFs recruit the BAF complex to enhancers to establish accessible chromatin
Natural genetic variation between divergent mouse strains reveals that enhancer selection requires the broadly expressed, growth-factor-inducible AP-1 TFs, which recruit the BAF chromatin remodeling complex to establish accessible chromatin. This demonstrates an essential role for external signals in determining which enhancers are selected in a given cell during development.
Known for nearly a century but through mechanisms that remain elusive, cells retain a memory of inflammation that equips them to react quickly and broadly to diverse secondary stimuli. Using murine ...epidermal stem cells as a model, we elucidate how cells establish, maintain, and recall inflammatory memory. Specifically, we landscape and functionally interrogate temporal, dynamic changes to chromatin accessibility, histone modifications, and transcription factor binding that occur during inflammation, post-resolution, and in memory recall following injury. We unearth an essential, unifying role for the general stress-responsive transcription factor FOS, which partners with JUN and cooperates with stimulus-specific STAT3 to establish memory; JUN then remains with other homeostatic factors on memory domains, facilitating rapid FOS re-recruitment and gene re-activation upon diverse secondary challenges. Extending our findings, we offer a comprehensive, potentially universal mechanism behind inflammatory memory and less discriminate recall phenomena with profound implications for tissue fitness in health and disease.
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•Stimulus-specific STAT3 and broad stress factor AP1 co-establish memory domains•Stem cell factors access open memory domains and remain bound after inflammation•FOS activates open memory domains, enabling secondary responses to diverse stimuli•AP1 mediates epigenetic inflammatory memory across cell types, stimuli, and species
Fuchs and colleagues couple high-throughput chromatin profiling with genetics to unravel the mechanisms of inflammatory memory establishment, maintenance, and recall. Stimulus-specific STAT3 and general stress factor FOS:JUN establish memory, enabling stem cell factors to access and maintain memory; upon diverse secondary challenges, FOS rapidly accesses memory domains to reactivate memory-associated transcription.
Epithelial cells: liaisons of immunity Larsen, Samantha B; Cowley, Christopher J; Fuchs, Elaine
Current opinion in immunology,
02/2020, Letnik:
62
Journal Article
Recenzirano
Odprti dostop
Epithelial cells sense danger launching a relay to immune cells to restore homeostasis within barrier tissues. Epithelial cells raise alarm to immune cells, which arrive on scene to aid epithelial ...cells in reinforcing barrier integrity. Following the race to restore homeostasis, epithelial cells display enhanced performance when they sense future danger. Created with BioRender.com.
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•Epithelial cells sense their microenvironment via an arsenal of pattern recognition receptors that inform downstream responses.•Microbial species tune epithelial-immune cell crosstalk to reinforce barrier integrity and/or mount host defense systems.•If a barrier tissue is breached, epithelial cells release alarmins that signal to the immune system for support.•After inflammation, epithelial cells retain chromatin accessibility at key immune loci that contribute to a heightened secondary response.
The surface and lining tissues of our body are exposed to the external environment, and as such these epithelial tissues must form structural barriers able to defend against microbes, environmental toxins, and mechanical stress. Their cells are equipped to detect a diverse array of surface perturbations, and then launch signaling relays to the immune system. The aim of these liaisons is to coordinate the requisite immune cell response needed to preserve and/or restore barrier integrity and defend the host. It has been recently appreciated that epithelial cells learn from these experiences. Following inflammatory exposure, long-lived stem cells within the tissue retain an epigenetic memory that endows them with heightened responsiveness to subsequent encounters with stress. Here, we review the recent literature on how epithelial cells sense signals from microbes, allergens, and injury at the tissue surface, and transmit this information to immune cells, while embedding a memory of the experience within their chromatin.
Histone deacetylases (HDACs) 1, 2 and 3 form the catalytic subunit of several large transcriptional repression complexes. Unexpectedly, the enzymatic activity of HDACs in these complexes has been ...shown to be regulated by inositol phosphates, which bind in a pocket sandwiched between the HDAC and co-repressor proteins. However, the actual mechanism of activation remains poorly understood. Here we have elucidated the stereochemical requirements for binding and activation by inositol phosphates, demonstrating that activation requires three adjacent phosphate groups and that other positions on the inositol ring can tolerate bulky substituents. We also demonstrate that there is allosteric communication between the inositol-binding site and the active site. The crystal structure of the HDAC1:MTA1 complex bound to a novel peptide-based inhibitor and to inositol hexaphosphate suggests a molecular basis of substrate recognition, and an entropically driven allosteric mechanism of activation.
Submillimetre galaxies (SMGs) are among the most luminous dusty galaxies in the Universe, but their true nature remains unclear; are SMGs the progenitors of the massive elliptical galaxies we see in ...the local Universe, or are they just a short-lived phase among more typical star-forming galaxies? To explore this problem further, we investigate the clustering of SMGs identified in the SCUBA-2 Cosmology Legacy Survey. We use a catalogue of submillimetre (850 mu m) source identifications derived using a combination of radio counterparts and colour/infrared selection to analyse a sample of 610 SMG counterparts in the United Kingdom Infrared Telescope (UKIRT) Infrared Deep Survey (UKIDSS) Ultra Deep Survey (UDS), making this the largest high-redshift sample of these galaxies to date. Using angular cross-correlation techniques, we estimate the halo masses for this large sample of SMGs and compare them with passive and star-forming galaxies selected in the same field. We find that SMGs, on average, occupy high-mass dark matter haloes ... at redshifts z > 2.5, consistent with being the progenitors of massive quiescent galaxies in present-day galaxy clusters. We also find evidence of downsizing, in which SMG activity shifts to lower mass haloes at lower redshifts. In terms of their clustering and halo masses, SMGs appear to be consistent with other star-forming galaxies at a given redshift. (ProQuest: ... denotes formulae/symbols omitted.)
We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. The most active degrader consists of a benzamide HDAC inhibitor, an alkyl linker, and the von Hippel-Lindau E3 ...ligand. Our PROTAC increased histone acetylation levels and compromised colon cancer HCT116 cell viability, establishing a degradation strategy as an alternative to class I HDAC inhibition.
MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle ...regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.
Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating
and
mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical ...function of the
gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an
SCLC cell line that conditionally expresses
to identify dependencies that are caused by RB1 loss and discovered that
SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other
cancers. SIGNIFICANCE: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that
SCLC are hyperdependent on
, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against
SCLC tumors in mice at nontoxic doses.
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