Chromatin remodeling protein BPTF mediates chromatin accessibility at gene promoters in planarian stem cells

The regulation of chromatin accessibility is essential in eukaryotic cells as one of several mechanisms that ensure gene activation occurs at appropriate times and in appropriate cell types. Accordingly, mutations in chromatin remodeling proteins are linked to many different developmental disorders and cancers. One example of a chromatin protein that has been linked to both developmental abnormalities and cancer is BPTF/NURF301, the largest subunit of the Nucleosome Remodeling Factor (NuRF) complex. The BPTF subunit is not only important for the formation of NuRF but also helps direct its activity to particular regions of chromatin by preferentially binding histone H3 lysine four trimethylation (H3K4me3). Notably, defects caused by knockdown of bptf in Xenopus embryos mimic those caused by knockdown of wdr5, a core subunit of all H3K4me3 methyltransferase complexes. However, the mechanistic details of how and where BPTF/NuRF is recruited to regulate gene expression vary between studies and have been largely tested in vitro and/or in cultured cells. Improving our understanding of how this chromatin remodeling complex targets specific gene loci and regulates their expression in an organismal context will provide important insight into how pathogenic mutations disrupt its normal, in vivo, cellular functions.

Here, we report our findings on the role of BPTF in maintaining chromatin accessibility and essential function in planarian (Schmidtea mediterranea) stem cells. We find that depletion of planarian BPTF primarily affects accessibility at gene promoters near transcription start sites (TSSs). BPTF-dependent loss of accessibility did not correlate with decreased gene expression when we considered all affected loci. However, we found that genes marked by Set1-dependent H3K4me3, but not MLL1/2-dependent H3K4me3, showed increased sensitivity to the loss of BPTF-dependent accessibility. In addition, knockdown of bptf (Smed-bptf) produces loss-of-function phenotypes similar to those caused by knockdown of Smed-set1.

The S.mediterranea homolog of NuRF protein BPTF (SMED-BPTF) is essential for normal homeostasis in planarian tissues, potentially through its role in maintaining chromatin accessibility at a specific subset of gene promoters in planarian stem cells. By identifying loci that lose both chromatin accessibility and gene expression after depletion of BPTF, we have identified a cohort of genes that may have important functions in stem cell biology.