ISWI Regulates Higher-Order Chromatin Structure and Histone H1 Assembly In Vivo

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Abstract
Imitation SWI (ISWI) and other ATP-dependent chromatin-remodeling factors play key roles in transcription and other processes by altering the structure and positioning of nucleosomes. Recent studies have also implicated ISWI in the regulation of higher-order chromatin structure, but its role in this process remains poorly understood. To clarify the role of ISWI in vivo, we examined defects in chromosome structure and gene expression resulting from the loss of Iswi function in Drosophila. Consistent with a broad role in transcriptional regulation, the expression of a large number of genes is altered in Iswi mutant larvae. The expression of a dominant-negative form of ISWI leads to dramatic alterations in higher-order chromatin structure, including the apparent decondensation of both mitotic and polytene chromosomes. The loss of ISWI function does not cause obvious defects in nucleosome assembly, but results in a significant reduction in the level of histone H1 associated with chromatin in vivo. These findings suggest that ISWI plays a global role in chromatin compaction in vivo by promoting the association of the linker histone H1 with chromatin. Chromatin-remodeling factors such as ISWI play a role in transcription and other nuclear processes by altering the structure and positioning of nucleosomes (the protein–DNA complexes that organize chromatin). Recent studies have suggested that chromatin-remodeling factors can also influence higher-order chromatin structure, but how they do this is not well understood. Using Drosophila melanogaster as a model organism, we investigated the role of ISWI in gene expression and the regulation of chromosome structure in higher eukaryotes. Loss of ISWI alters the expression of a large number of genes. The loss of ISWI function also causes dramatic alterations in higher-order chromatin structure—including the decondensation of mitotic and polytene chromosomes—accompanied by a striking reduction in the amount of the linker histone H1 associated with chromatin. Based on these findings, we propose that ISWI plays a global role in chromosome compaction by promoting the association of a linker histone with chromatin.