Heterochromatin Protein HP1α Gelation Dynamics Revealed by Solid‐State NMR Spectroscopy

Ackermann, Bryce E.; Debelouchina, Galia T.

doi:10.1002/anie.201901141

Cited by 54 publications

(41 citation statements)

References 34 publications

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“…[5,6] For instance, binding of the IDR-containing heterochromatin protein HP1α to the histone H3K9 methylation site induces LLPS in specific domains of heterochromatin. [8][9][10][11] LLPS also occurs in euchromatin regions that are rich in acetylated histone tails when the transcriptional regulator protein BRD4, which contains a long IDR, is co-localized. [12,13] Thus, the nature of the relationship between LLPS-mediated chromatin-condensation and proteins is gradually determined.…”

Section: Introductionmentioning

confidence: 99%

Quadruplex folding promotes the condensation of linker histones and DNAs via liquid-liquid phase separation

Mimura¹,

Tomita

Shinkai³

et al. 2021

Preprint

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<p>Liquid-liquid phase separation (LLPS) of proteins and DNA has recently emerged as a possible mechanism underlying the dynamic organization of chromatin. We herein report the role of DNA quadruplex folding in liquid droplet formation via LLPS induced by interactions between DNA and linker histone H1 (H1), a key regulator of chromatin organization. Fluidity measurements inside the droplets and binding assays using G-quadruplex-selective probes demonstrated that quadruplex DNA structures, such as the G-quadruplex and i-motif, promote droplet formation with H1 and decrease molecular motility within droplets. The dissolution of the droplets in the presence of additives indicated that in addition to electrostatic interactions between the DNA and the intrinsically disordered region of H1, π-π stacking between quadruplex DNAs could potentially drive droplet formation. Given that DNA quadruplex structures are well documented in heterochromatin regions, it is imperative to understand the role of DNA quadruplex folding in the context of intranuclear LLPS.<b></b></p>

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Section: Introductionmentioning

confidence: 99%

Quadruplex folding promotes the condensation of linker histones and DNAs via liquid-liquid phase separation

Mimura¹,

Tomita

Shinkai³

et al. 2021

Preprint

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“…Hence, direct insights into the structural and dynamical organization of liquid-like droplets has been limited 12 . Instead, solid-state NMR (ssNMR) has been employed to study formation 13,14 and structural organization 13,15–19 of protein hydrogels and fibrillar assemblies that may be closely related to LLPS 3,20 . For example, we have previously used ssNMR to investigate the hydrogel state of the FG repeat domain of the nucleoporin Nsp1p, revealing that transient amyloid-like β-sheet interactions among NTQS-rich protein regions are responsible for gelation and network formation 13,16 .…”

Section: Introductionmentioning

confidence: 99%

Atomic-level insight into mRNA processing bodies by combining solid and solution-state NMR spectroscopy

et al. 2019

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Liquid–liquid phase separation is increasingly recognized as a process involved in cellular organization. Thus far, a detailed structural characterization of this intrinsically heterogeneous process has been challenging. Here we combine solid- and solution-state NMR spectroscopy to obtain atomic-level insights into the assembly and maturation of cytoplasmic processing bodies that contain mRNA as well as enzymes involved in mRNA degradation. In detail, we have studied the enhancer of decapping 3 (Edc3) protein that is a central hub for processing body formation in yeast. Our results reveal that Edc3 domains exhibit diverse levels of structural organization and dynamics after liquid–liquid phase separation. In addition, we find that interactions between the different Edc3 domains and between Edc3 and RNA in solution are largely preserved in the condensed protein state, allowing processing bodies to rapidly form and dissociate upon small alterations in the cellular environment.

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“…Single cell sequencing has convincingly shown that nucleosome positioning is not consistent between cells in a population (30)(31)(32). Heterochromatin domains comprising phase-separated droplets are now known to be more dynamic than previously assumed (33,34). Chromatin interactions are similarly variegated: the frequency of DNA loop formation is approximately 30% of alleles at maximum depending on the locus and RNAPII-mediated loops are heterogeneous (35)(36)(37).…”

Section: Small Variable Domains Of Chromatin Structure Facilitate Heterogeneity and Inducibilitymentioning

confidence: 99%

Immune Regulation in Time and Space: The Role of Local- and Long-Range Genomic Interactions in Regulating Immune Responses

2021

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Mammals face and overcome an onslaught of endogenous and exogenous challenges in order to survive. Typical immune cells and barrier cells, such as epithelia, must respond rapidly and effectively to encountered pathogens and aberrant cells to prevent invasion and eliminate pathogenic species before they become overgrown and cause harm. On the other hand, inappropriate initiation and failed termination of immune cell effector function in the absence of pathogens or aberrant tissue gives rise to a number of chronic, auto-immune, and neoplastic diseases. Therefore, the fine control of immune effector functions to provide for a rapid, robust response to challenge is essential. Importantly, immune cells are heterogeneous due to various factors relating to cytokine exposure and cell-cell interaction. For instance, tissue-resident macrophages and T cells are phenotypically, transcriptionally, and functionally distinct from their circulating counterparts. Indeed, even the same cell types in the same environment show distinct transcription patterns at the single cell level due to cellular noise, despite being robust in concert. Additionally, immune cells must remain quiescent in a naive state to avoid autoimmunity or chronic inflammatory states but must respond robustly upon activation regardless of their microenvironment or cellular noise. In recent years, accruing evidence from next-generation sequencing, chromatin capture techniques, and high-resolution imaging has shown that local- and long-range genome architecture plays an important role in coordinating rapid and robust transcriptional responses. Here, we discuss the local- and long-range genome architecture of immune cells and the resultant changes upon pathogen or antigen exposure. Furthermore, we argue that genome structures contribute functionally to rapid and robust responses under noisy and distinct cellular environments and propose a model to explain this phenomenon.

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Heterochromatin Protein HP1α Gelation Dynamics Revealed by Solid‐State NMR Spectroscopy

Abstract: Heterochromatin protein 1a (HP1a)u ndergoes liquid-liquid phase separation (LLPS) and forms liquid droplets and gels in vitro,p roperties that also appear to be

Cited by 54 publications

References 34 publications

Quadruplex folding promotes the condensation of linker histones and DNAs via liquid-liquid phase separation

Quadruplex folding promotes the condensation of linker histones and DNAs via liquid-liquid phase separation

Atomic-level insight into mRNA processing bodies by combining solid and solution-state NMR spectroscopy

Immune Regulation in Time and Space: The Role of Local- and Long-Range Genomic Interactions in Regulating Immune Responses

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