Dissecting the Role of ISWI Chromatin Remodellers in Inflammatory Gene Expression

Alomà, Júlia Melià (2021). Dissecting the Role of ISWI Chromatin Remodellers in Inflammatory Gene Expression. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00012824

Abstract

The inflammatory response is driven by a highly accurate and kinetically complex transcriptional program that is controlled by the stimulus-regulated usage of thousands of cis-regulatory elements (i.e. enhancers and promoters). Stimulus-activated transcription factors (TFs) involved in this response, as well as their interplay with lineage-determining TFs, have been extensively characterised. However, the role of different families of coregulators that are recruited by those TFs in most cases remains to be elucidated. In light of this, I set out to dissect the role of a specific family of co-regulators, namely the ISWI family of ATP-dependent chromatin remodellers, in modulating the transcriptional response to inflammatory stimuli such as lipopolysaccharide (LPS) in bone marrow-derived mouse macrophages. By combining transcriptomic and other genomic experiments and analyses, I have found that ISWI complexes present in innate immune cells are involved in the regulation of different components of the transcriptional program of murine macrophages. On one hand, I found that ISWI complexes are strongly associated with the regulation of the interferon response. By ChIP-seq analysis, I show that distinct ISWI subunits are recruited to regulatory regions bound by Interferon Regulatory Factors (IRFs), where they control the epigenomic landscape and thus regulate the interferon gene expression program. On the other hand, by ATAC-seq analysis I also identified a large set of genomic regions which are maintained in a repressed state in the presence of the ISWI catalytic subunit SMARCA5. However, these regions are not occupied by SMARCA5, indicating that in this case it is not the direct action of the ATPase
which controls the chromatin state.

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