Dataset Information

Transcription factor Znf2 coordinates with the chromatin remodeling SWI/SNF complex to regulate cryptococcal cellular differentiation.

ABSTRACT: Cellular differentiation is instructed by developmental regulators in coordination with chromatin remodeling complexes. Much information about their coordination comes from studies in the model ascomycetous yeasts. It is not clear, however, what kind of information that can be extrapolated to species of other phyla in Kingdom Fungi. In the basidiomycete Cryptococcus neoformans, the transcription factor Znf2 controls yeast-to-hypha differentiation. Through a forward genetic screen, we identified the basidiomycete-specific factor Brf1. We discovered Brf1 works together with Snf5 in the SWI/SNF chromatin remodeling complex in concert with existent Znf2 to execute cellular differentiation. We demonstrated that SWI/SNF assists Znf2 in opening the promoter regions of hyphal specific genes, including the ZNF2 gene itself. This complex also supports Znf2 to fully associate with its target regions. Importantly, our findings revealed key differences in composition and biological function of the SWI/SNF complex in the two major phyla of Kingdom Fungi.

SUBMITTER: Lin J

PROVIDER: S-EPMC6856107 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Transcription factor Znf2 coordinates with the chromatin remodeling SWI/SNF complex to regulate cryptococcal cellular differentiation.

Lin Jianfeng J Zhao Youbao Y Ferraro Aileen R AR Yang Ence E Lewis Zachary A ZA Lin Xiaorong X

Communications biology 20191114

Cellular differentiation is instructed by developmental regulators in coordination with chromatin remodeling complexes. Much information about their coordination comes from studies in the model ascomycetous yeasts. It is not clear, however, what kind of information that can be extrapolated to species of other phyla in Kingdom Fungi. In the basidiomycete <i>Cryptococcus neoformans</i>, the transcription factor Znf2 controls yeast-to-hypha differentiation. Through a forward genetic screen, we iden ...[more]

PMID: 31754642

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Project description:Chromatin remodelers such as the SWI/SNF complex coordinate metazoan development through broad regulation of chromatin accessibility and transcription, ensuring normal cell cycle control and cellular differentiation in a lineage-specific and temporally restricted manner. Mutations in genes encoding the structural subunits of chromatin, such as histone subunits, and chromatin regulating factors are associated with a variety of disease mechanisms including cancer metastasis, in which cancer co-opts cellular invasion programs functioning in healthy cells during development. Here we utilize Caenorhabditis elegans anchor cell (AC) invasion as an in vivo model to identify the suite of chromatin agents and chromatin regulating factors that promote cellular invasiveness. We demonstrate that the SWI/SNF ATP-dependent chromatin remodeling complex is a critical regulator of AC invasion, with pleiotropic effects on both G0 cell cycle arrest and activation of invasive machinery. Using targeted protein degradation and enhanced RNA interference (RNAi) vectors, we show that SWI/SNF contributes to AC invasion in a dose-dependent fashion, with lower levels of activity in the AC corresponding to aberrant cell cycle entry and increased loss of invasion. Our data specifically implicate the SWI/SNF BAF assembly in the regulation of the G0 cell cycle arrest in the AC, whereas the SWI/SNF PBAF assembly promotes AC invasion via cell cycle-independent mechanisms, including attachment to the basement membrane (BM) and activation of the pro-invasive fos-1/FOS gene. Together these findings demonstrate that the SWI/SNF complex is necessary for two essential components of AC invasion: arresting cell cycle progression and remodeling the BM. The work here provides valuable single-cell mechanistic insight into how the SWI/SNF assemblies differentially contribute to cellular invasion and how SWI/SNF subunit-specific disruptions may contribute to tumorigeneses and cancer metastasis.

Project description:Human immunodeficiency virus type 1 (HIV-1) is the etiologic agent of acquired immunodeficiency virus (AIDS). Following entry into the host cell, the viral RNA is reverse transcribed into DNA and subsequently integrated into the host genome as a chromatin template. The integrated proviral DNA, along with the specific chromatinized environment in which integration takes place allows for the coordinated regulation of viral transcription and replication. While the specific roles of and interplay between viral and host proteins have not been fully elucidated, numerous reports indicate that HIV-1 retains the ability for self-regulation via the pleiotropic effects of its viral proteins. Though viral transcription is fully dependent upon host cellular factors and the state of host activation, recent findings indicate a complex interplay between viral proteins and host transcription regulatory machineries including histone deacetylases (HDACs), histone acetyltransferases (HATs), cyclin dependent kinases (CDKs), and histone methyltransferases (HMTs).Here, we describe the effect of Tat activated transcription at the G1/S border of the cell cycle and analyze the interaction of modified Tat with the chromatin remodeling complex, SWI/SNF. HIV-1 LTR DNA reconstituted into nucleosomes can be activated in vitro using various Tat expressing extracts. Optimally activated transcription was observed at the G1/S border of the cell cycle both in vitro and in vivo, where chromatin remodeling complex, SWI/SNF, was present on the immobilized LTR DNA. Using a number of in vitro binding as well as in vivo chromatin immunoprecipitation (ChIP) assays, we detected the presence of both BRG1 and acetylated Tat in the same complex. Finally, we demonstrate that activated transcription resulted in partial or complete removal of the nucleosome from the start site of the LTR as evidenced by a restriction enzyme accessibility assay.We propose a model where unmodified Tat is involved in binding to the CBP/p300 and cdk9/cyclin T1 complexes facilitating transcription initiation. Acetylated Tat dissociates from the TAR RNA structure and recruits bromodomain-binding chromatin modifying complexes such as p/CAF and SWI/SNF to possibly facilitate transcription elongation.

Dataset Information

Transcription factor Znf2 coordinates with the chromatin remodeling SWI/SNF complex to regulate cryptococcal cellular differentiation.

Publications

Transcription factor Znf2 coordinates with the chromatin remodeling SWI/SNF complex to regulate cryptococcal cellular differentiation.

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