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The Sky's the LEMit: New insights into nuclear structure regulation of transcription factor activity.

ABSTRACT: The nucleoskeleton has been associated with partitioning the genome into active and inactive compartments that dictate local transcription factor (TF) activity. However, recent data indicate that the nucleoskeleton and TFs reciprocally influence each other in dynamic TF trafficking pathways through the functions of LEM proteins. While the conserved peripheral recruitment of TFs by LEM proteins has been viewed as a mechanism of repressing transcription, a diversity of release mechanisms from the lamina suggest this compartment serves as a refuge for nuclear TF accumulation for rapid mobilization and signal stability. Detailed mechanisms suggest that TFs toggle between nuclear lamina refuge and nuclear matrix lamin-LEM protein complexes at sites of active transcription. In this review we will highlight emerging LEM functions acting at the interface of chromatin and nucleoskeleton to create TF trafficking networks.

SUBMITTER: Mirza AN

PROVIDER: S-EPMC7925346 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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The Sky's the LEMit: New insights into nuclear structure regulation of transcription factor activity.

Mirza Amar N AN Gonzalez Fernanda F Ha Sierra K SK Oro Anthony E AE

Current opinion in cell biology 20201120

The nucleoskeleton has been associated with partitioning the genome into active and inactive compartments that dictate local transcription factor (TF) activity. However, recent data indicate that the nucleoskeleton and TFs reciprocally influence each other in dynamic TF trafficking pathways through the functions of LEM proteins. While the conserved peripheral recruitment of TFs by LEM proteins has been viewed as a mechanism of repressing transcription, a diversity of release mechanisms from the ...[more]

PMID: 33227657

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Project description:The fungal kingdom has provided advances in our ability to identify biosynthetic gene clusters (BGCs) and to examine how gene composition of BGCs evolves across species and genera. However, little is known about the evolution of specific BGC regulators that mediate how BGCs produce secondary metabolites (SMs). A bioinformatics search for conservation of the Aspergillus fumigatus xanthocillin BGC revealed an evolutionary trail of xan-like BGCs across Eurotiales species. Although the critical regulatory and enzymatic genes were conserved in Penicillium expansum, overexpression (OE) of the conserved xan BGC transcription factor (TF) gene, PexanC, failed to activate the putative xan BGC transcription or xanthocillin production in P. expansum, in contrast to the role of AfXanC in A. fumigatus. Surprisingly, OE::PexanC was instead found to promote citrinin synthesis in P. expansum via trans induction of the cit pathway-specific TF, ctnA, as determined by cit BGC expression and chemical profiling of ctnA deletion and OE::PexanC single and double mutants. OE::AfxanC results in significant increases of xan gene expression and metabolite synthesis in A. fumigatus but had no effect on either xanthocillin or citrinin production in P. expansum. Bioinformatics and promoter mutation analysis led to the identification of an AfXanC binding site, 5'-AGTCAGCA-3', in promoter regions of the A. fumigatus xan BGC genes. This motif was not in the ctnA promoter, suggesting a different binding site of PeXanC. A compilation of a bioinformatics examination of XanC orthologs and the presence/absence of the 5'-AGTCAGCA-3' binding motif in xan BGCs in multiple Aspergillus and Penicillium spp. supports an evolutionary divergence of XanC regulatory targets that we speculate reflects an exaptation event in the Eurotiales. IMPORTANCE Fungal secondary metabolites (SMs) are an important source of pharmaceuticals on one hand and toxins on the other. Efforts to identify the biosynthetic gene clusters (BGCs) that synthesize SMs have yielded significant insights into how variation in the genes that compose BGCs may impact subsequent metabolite production within and between species. However, the role of regulatory genes in BGC activation is less well understood. Our finding that the bZIP transcription factor XanC, located in the xanthocillin BGC of both Aspergillus fumigatus and Penicillium expansum, has functionally diverged to regulate different BGCs in these two species emphasizes that the diversification of BGC regulatory elements may sometimes occur through exaptation, which is the co-option of a gene that evolved for one function to a novel function. Furthermore, this work suggests that the loss/gain of transcription factor binding site targets may be an important mediator in the evolution of secondary-metabolism regulatory elements.

Dataset Information

The Sky's the LEMit: New insights into nuclear structure regulation of transcription factor activity.

Publications

The Sky's the LEMit: New insights into nuclear structure regulation of transcription factor activity.

Similar Datasets

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