Chao Lu

Co-culture with stellate ganglia (SG) promotes the growth of mouse SCLC

ICI treatment reduces the growth of SCLC

PKA inhibition (PKAi) reduces the growth of primary human SCLC cells

High levels of ADRB2 promote the growth of mouse SCLC

ADRB2 regulates the growth of human SCLC cells

Sympathetic and parasympathetic nerve fibers in mouse SCLC

Polycomb repressive complex 2 (PRC2)-mediated histone H3 K27 trimethylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, Polycomb-regulated genes can display long-range three-dimensional interactions, many of which resolve during lineage differentiation. Here we report that Polycomb-anchored looping is controlled by H3K27me3 spreading and regulates target gene silencing to influence cell fate specification. Using glioma-derived H3 Lys27-to-Met (H3K27M) mutations as tools to restrict H3K27me3 spreading, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened three-dimensional interactions that mirror the chromatin architecture of pluripotency. Conversely, H3K27me3 spread in pluripotent stem cells dilutes local cPRC1 chromatin concentration, weakening Polycomb loop contact frequencies. Disruption of cPRC1 binding or aggregation compromises stringent repression of Polycomb genes and induces differentiation and tumor regression of H3K27M-mutant glioma. These results identify the regulatory principles and disease implications of Polycomb looping and show that histone-modification-guided distribution of reader complexes is an important mechanism for nuclear compartment organization.

Tissue-resident lymphocytes can recirculate, but the underlying molecular mechanism is poorly understood. During helminth infection, intestinal group 2 innate lymphoid cells (ILC2s) rapidly proliferate and give rise to inflammatory ILC2s (iILC2s), which migrate from the intestine to distal tissues. Here, we show in mice that the redistribution of iILC2s requires access to lymphatic vessels. Interleukin-25 (IL-25) induces a substantial change in the epigenetic landscape of iILC2s, with transcription factors KLF2 and ZEB2 driving increased expression of sphingosine-1-phosphate receptor 1 (S1PR1) and S1PR5, respectively. S1PR5 regulates iILC2 exit from the intestine to the lymph, whereas S1PR1 is critical for iILC2 egress from the mesenteric lymph nodes to the blood and then to distal tissues including the lung, where iILC2s contribute to tissue repair. The requirement of two S1PRs is largely due to the dynamic expression of CD69, which mediates S1PR1 internalization. Thus, S1PRs modulate iILC2 emigration from nonlymphoid and lymphoid organs in a stage-specific manner, which provides a framework for understanding the multistep migration of tissue-resident immune cells.

DNA methyltransferase DNMT3A-mediated DNA methylation is important for genomic imprinting and transcriptional regulation. However, how the regulatory domains of DNMT3A cooperate with its methyltransferase domain and histone marks to orchestrate genomic methylation remains unclear. Here we report the cryo-EM structure of DNMT3A2 with regulatory factor DNMT3L, revealing an intricate domain interaction underlying multilayered autoinhibition. The PWWP domain interacts with the ADD and methyltransferase domains to block the target recognition domain and the H3K36me2-binding pocket, thereby coupling the H3K36me2 binding with DNMT3A activation, adding a layer of allosteric regulation distinct from the previously characterized ADD-H3K4me0 regulation. Molecular dynamics simulations of the DNMT3A-DNMT3L complex further reveals that relief of DNMT3A autoinhibition involves disengagement of the CpG-recognition loop of the target recognition domain from autoinhibitory interaction, leading to enhanced accessibility of the target recognition domain loop for DNA binding and DNMT3A activation. Importantly, our combined structural, biochemical and genomic methylation analysis demonstrates that disrupting the PWWP-ADD interaction by disease-associated DNMT3A mutations leads to impaired DNMT3A autoinhibition and substrate specificity, providing a potential explanation to aberrant DNA methylation in disease.