Mll1 pioneers histone H3K4me3 deposition and promotes formation of CD8 + T stem cell memory.

CD8 + T cells with stem cell-like properties (T SCM ) sustain adaptive immunity to intracellular pathogens and tumors. However, the developmental origins and chromatin regulatory factors (CRFs) that establish their differentiation are unclear. Using an RNA interference screen of all CRFs we discovered the histone methylase Mll1 was required during T cell receptor (TCR) stimulation for development of a T SCM precursor state and mature memory (T MEM ) cells, but not short-lived or transitory effector cell-like states, in response to viral infections and tumors. Mll1 was essential for widespread de novo deposition of histone H3 lysine 4 trimethylation (H3K4me3) upon TCR stimulation, which accounted for 70% of all activation-induced sites in mature T MEM cells. Mll1 promoted both H3K4me3 deposition and reduced TCR-induced Pol II pausing at genes whose single-cell transcriptional dynamics explained trajectories into nascent T SCM precursor states during viral infection. Our results suggest Mll1-dependent control of Pol II elongation and H3K4me3 establishes and maintains differentiation of CD8 + T SCM cell states.

Methylation changes in the peripheral blood of Filipinos with type 2 diabetes suggest spurious transcription initiation at TXNIP.

While much work has been done in associating differentially methylated positions (DMPs) to type 2 diabetes (T2D) across different populations, not much attention has been placed on identifying its possible functional consequences. We explored methylation changes in the peripheral blood of Filipinos with T2D and identified 177 associated DMPs. Most of these DMPs were associated with genes involved in metabolism, inflammation and the cell cycle. Three of these DMPs map to the TXNIP gene body, replicating previous findings from epigenome-wide association studies (EWAS) of T2D. The TXNIP downmethylation coincided with increased transcription at the 3' UTR, H3K36me3 histone markings and Sp1 binding, suggesting spurious transcription initiation at the TXNIP 3' UTR as a functional consequence of T2D methylation changes. We also explored potential epigenetic determinants to increased incidence of T2D in Filipino immigrants in the USA and found three DMPs associated with the interaction of T2D and immigration. Two of these DMPs were located near MAP2K7 and PRMT1, which may point towards dysregulated stress response and inflammation as a contributing factor to T2D among Filipino immigrants.