Chromatin modules and their implication in genomic organization and gene regulation.

ABSTRACT Transcription is the fundamental process of gene expression, which in eukaryotes occurs within the complex physicochemical environment of the nucleus. Decades of research have provided extreme detail in the molecular and functional mechanisms of transcription, but the spatial and genomic organization of transcription remains mysterious. Recent discoveries show that transcriptional components can undergo phase separation and create distinct compartments inside the nucleus, providing new models through which to view the transcription process in eukaryotes. In this review, we focus on transcriptional condensates and their phase separation-like behaviors. We suggest differentiation between physical descriptions of phase separation and the complex and dynamic biomolecular assemblies required for productive gene expression, and we discuss how transcriptional condensates are central to organizing the three-dimensional genome across spatial and temporal scales. Finally, we map approaches for therapeutic manipulation of transcriptional condensates and ask what technical advances are needed to understand transcriptional condensates more completely.

https://www.tandfonline.com/doi/pdf/10.1080/19491034.2023.2213551?needAccess=true&role=button

Transcriptional condensates and phase separation: condensing information across scales and mechanisms

ABSTRACT Enhancers are cis-regulatory elements that can stimulate gene expression from distance, and drive precise spatiotemporal gene expression profiles during development. Functional enhancers display specific features including an open chromatin conformation, Histone H3 lysine 27 acetylation, Histone H3 lysine 4 mono-methylation enrichment, and enhancer RNAs production. These features are modified upon developmental cues which impacts their activity. In this review, we describe the current state of knowledge about enhancer functions and the diverse chromatin signatures found on enhancers. We also discuss the dynamic changes of enhancer chromatin signatures, and their impact on lineage specific gene expression profiles, during development or cellular differentiation.

The chromatin signatures of enhancers and their dynamic regulation

Intracellular liquid–liquid phase separation (LLPS) is a critical process involving the dynamic association of biomolecules and the formation of non-membrane compartments, playing a vital role in regulating biomolecular interactions and organelle functions. A comprehensive understanding of cellular LLPS mechanisms at the molecular level is crucial, as many diseases are linked to LLPS, and insights gained can inform drug/gene delivery processes and aid in the diagnosis and treatment of associated diseases. Over the past few decades, numerous techniques have been employed to investigate the LLPS process. In this review, we concentrate on optical imaging methods applied to LLPS studies. We begin by introducing LLPS and its molecular mechanism, followed by a review of the optical imaging methods and fluorescent probes employed in LLPS research. Furthermore, we discuss potential future imaging tools applicable to the LLPS studies. This review aims to provide a reference for selecting appropriate optical imaging methods for LLPS investigations.

/pdf/study-liquid-liquid-phase-separation-with-optical-microscopy-3fu89wfe.pdf

Study liquid–liquid phase separation with optical microscopy: A methodology review

Abstract The Th2 cytokine interleukin 4 (IL4) promotes macrophage differentiation into alternative subtypes and plays important roles in physiology, in metabolic and inflammatory diseases, in cancer and in tissue regeneration. While the regulatory transcription factor networks governing IL4 signaling are already well-characterized, it is currently less understood which transcriptional coregulators are involved and how they operate mechanistically. In this study, we discover that G protein pathway suppressor 2 (GPS2), a core subunit of the HDAC3 corepressor complex assembled by SMRT and NCOR, represses IL4-dependent enhancer activation in mouse macrophages. Our genome-wide and gene-specific characterization revealed that, instead of directly repressing STAT6, chromatin-bound GPS2 cooperates with SMRT and NCOR to antagonize enhancer activation by lysine demethylase 1A (KDM1A, LSD1). Mechanistically, corepressor depletion increased KDM1A recruitment to enhancers linked to IL4-induced genes, accompanied by demethylation of the repressive histone marks H3K9me2/3 without affecting H3K4me1/2, the classic KDM1A substrates for demethylation in other cellular contexts. This in turn caused enhancer and gene activation already in the absence of IL4/STAT6 and sensitized the STAT6-dependent IL4 responsiveness of macrophages. Thus, our work identified with the antagonistic action of a GPS2-containing corepressor complex and the lysine demethylase KDM1A a hitherto unknown epigenetic corepressor-coactivator switching mechanism that governs alternative macrophage activation.

/pdf/antagonistic-action-of-gps2-and-kdm1a-at-enhancers-governs-3utgtdbi.pdf

Antagonistic action of GPS2 and KDM1A at enhancers governs alternative macrophage activation by interleukin 4

Super-enhancers (SEs) govern macrophage polarization and function. However, the mechanism underlying the signal-dependent latent SEs remodeling in macrophages remains largely undefined. Here we show that the epigenetic reader ZMYND8 forms liquid compartments with NF-κB/p65 to silence latent SEs and restrict macrophage-mediated inflammation. Mechanistically, the fusion of ZMYND8 and p65 liquid condensates is reinforced by signal-induced acetylation of p65. Then acetylated p65 guides the ZMYND8 redistribution onto latent SEs de novo generated in polarized macrophages, and consequently, recruit LSD1 to decommission latent SEs. The liquidity characteristic of ZMYND8 is critical for its regulatory effect since mutations coagulating ZMYND8 into solid compartments disable the translocation of ZMYND8 and its suppressive function. Thereby, ZMYND8 serves as a molecular rheostat to switch off latent SEs and control the magnitude of the immune response. Meanwhile, we propose a phase separation model by which the latent SEs are fine-tuned in a spatiotemporal manner.

ZMYND8 mediated liquid condensates spatiotemporally decommission the latent super-enhancers during macrophage polarization.

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ZMYND8 mediated liquid condensates spatiotemporally decommission the latent super-enhancers during macrophage polarization.