The liquid-liquid phase separation (LLPS) of proteins and nucleic acids is a biological process that has been recently shown to play a critical role in the organization of membraneless intracellular compartments. Recent studies have revealed that the several subcompartments of the nucleus, once thought to be a physically homogeneous structure, are also formed through LLPS. These include, for instance, the nucleoli and the Cajal bodies, which are essential for gene expression and RNA processing. LLPS is a well-suited mechanism for the organization of subnuclear comparments because it allows the local concentration of specific molecular components within the relatively small nuclear volume: this segregation of molecules can help increase reaction rates in a spatially and temporally controlled manner. Indeed, LLPS can also create dynamic and reversible compartments that can respond rapidly to changes in cellular conditions or, when persisting more stably, encode cellular ‘memories’. This enables the nucleus to adapt to various stimuli and stressors, such as DNA damage or to change gene expression patterns in a more or less persistent manner. The objective of this study is to provide an overview of the latest research findings and discoveries on the involvement of LLPS in the preservation of the structure and function of various nuclear compartments. First, I have analyzed the role of LLPS in the formation of heterochromatin domains. In particular, several studies suggest that LLPS is a major mechanism of this process, and experimentally identify the key proteins that mediate it. They show that in vivo heterochromatin formation involves HP1 undergoing dynamic changes typical of LLPS-prone proteins, but disagree concerning the exact mechanism. One study concludes that HP1 can be undergo LLPS driven by intrinsically disordered regions (IDRs) in its N-terminus and hinge domain. Other studies propose indeed that the complexes of HP1 with other proteins like scaffold factors and SUV39H1 are required, and that the key multivalent interaction in heterochromatin LLPS is the chromatin binding via chromodomains, ich whpresent in multiple proteins. Second, another study that I analyzed discusses the interconnection between constitutive heterochromatin (PCH) and nucleoli, as two membraneless organelles formed via LLPS. This research discovered a link between the functional state of HP1 dimers in PCH and nucleolar structure integrity. The authors suggest that H3K9me3 and HP1 proteins at PCH play a critical role in conferring functional sovereignty to PCH and nucleoli by modulating the biophysical properties of chromocenters and preventing major satellite repeat transcription from "escaping" into neighboring nuclear domains. Overall, this analysis highlights how LLPS can play a critical role in forming and maintaining various nuclear domains. These findings advance our understanding of the regulation of gene expression, and have implications for various human diseases of genetic origin.

Il ruolo della separazione di fase liquido-liquido nel mantenimento delle memorie cellulari.

IVANNIKOVA, DARIA
2021/2022

Abstract

The liquid-liquid phase separation (LLPS) of proteins and nucleic acids is a biological process that has been recently shown to play a critical role in the organization of membraneless intracellular compartments. Recent studies have revealed that the several subcompartments of the nucleus, once thought to be a physically homogeneous structure, are also formed through LLPS. These include, for instance, the nucleoli and the Cajal bodies, which are essential for gene expression and RNA processing. LLPS is a well-suited mechanism for the organization of subnuclear comparments because it allows the local concentration of specific molecular components within the relatively small nuclear volume: this segregation of molecules can help increase reaction rates in a spatially and temporally controlled manner. Indeed, LLPS can also create dynamic and reversible compartments that can respond rapidly to changes in cellular conditions or, when persisting more stably, encode cellular ‘memories’. This enables the nucleus to adapt to various stimuli and stressors, such as DNA damage or to change gene expression patterns in a more or less persistent manner. The objective of this study is to provide an overview of the latest research findings and discoveries on the involvement of LLPS in the preservation of the structure and function of various nuclear compartments. First, I have analyzed the role of LLPS in the formation of heterochromatin domains. In particular, several studies suggest that LLPS is a major mechanism of this process, and experimentally identify the key proteins that mediate it. They show that in vivo heterochromatin formation involves HP1 undergoing dynamic changes typical of LLPS-prone proteins, but disagree concerning the exact mechanism. One study concludes that HP1 can be undergo LLPS driven by intrinsically disordered regions (IDRs) in its N-terminus and hinge domain. Other studies propose indeed that the complexes of HP1 with other proteins like scaffold factors and SUV39H1 are required, and that the key multivalent interaction in heterochromatin LLPS is the chromatin binding via chromodomains, ich whpresent in multiple proteins. Second, another study that I analyzed discusses the interconnection between constitutive heterochromatin (PCH) and nucleoli, as two membraneless organelles formed via LLPS. This research discovered a link between the functional state of HP1 dimers in PCH and nucleolar structure integrity. The authors suggest that H3K9me3 and HP1 proteins at PCH play a critical role in conferring functional sovereignty to PCH and nucleoli by modulating the biophysical properties of chromocenters and preventing major satellite repeat transcription from "escaping" into neighboring nuclear domains. Overall, this analysis highlights how LLPS can play a critical role in forming and maintaining various nuclear domains. These findings advance our understanding of the regulation of gene expression, and have implications for various human diseases of genetic origin.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14240/139691