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CHD4/dMi-2 complexes & regulation of gene expression

Jonathan Lenz, Laura Schmelzer

CHD4 is an ATP-dependent remodeller that modifies chromatin structure by sliding nucleosomes along the genome. This change in nucleosome density impacts many DNA-related processes like the transcription of genes and DNA repair. To facilitate these functions, CHD4 interacts with other chromatin regulators and transcription factors.

The Drosophila homolog of CHD4, dMi-2, is part of at least two distinct protein complexes: dNuRD and dMec. Both of these assemblies regulate gene expression and bind to chromatin. They are crucial for Drosophila development and differentiation of many specialised cell-types. Although we find that dMi-2 occupies distinct loci in the genome, none of the complex components have a known sequence preference in their DNA-binding.

This evokes the long standing question: How are chromatin regulators without sequence-specificity, like dMi-2, guided to their chromatin targets? We hypothesise that other DNA-binding proteins, that possess a sequence preference, tether dMi-2 to its target loci. To address this, we employ proteomic approaches (endogenous tagging using CRISPR/Cas9, immunoprecipitation, mass spectrometry, Western blot) to characterise novel dMi-2 interactors. Using next-generation sequencing (RNA-seq, ChIP-seq) we uncover genes and pathways that are regulated by dMi-2 and its associated factors.

In doing so we have found so far unknown cooperations of dMi-2 with transcription factors that function for example in steroid hormone response (Kreher et al., 2017), spermatogenesis (Kim et al., 2017) and hematopoiesis (Lenz et al., 2021).