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MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post‐transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post‐translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip‐mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri‐methylation promotes tumor glycolysis and M2‐like polarization of tumor‐associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri‐methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1‐mediated tri‐methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC. [ABSTRACT FROM AUTHOR]

Abstract In eukaryote cells, core components of chromatin, such as histones and DNA, are packaged in nucleus. Leakage of nuclear materials into cytosol will induce pathological effects. However, the underlying mechanisms remain elusive. Here, cytoplasmic localization of nuclear materials induced by chromatin dysregulation (CLIC) in mammalian cells is reported. H3K9me3 inhibition by small chemicals, HP1α knockdown, or knockout of H3K9 methylase SETDB1, induces formation of cytoplasmic puncta containing histones H3.1, H4 and cytosolic DNA, which in turn activates inflammatory genes and autophagic degradation. Autophagy deficiency rescues H3 degradation, and enhances the activation of inflammatory genes. MRE11, a subunit of MRN complex, enters cytoplasm after heterochromatin dysregulation. Deficiency of MRE11 or NBS1, but not RAD50, inhibits CLIC puncta in cytosol. MRE11 depletion represses tumor growth enhanced by HP1α deficiency, suggesting a connection between CLIC and tumorigenesis. This study reveals a novel pathway that heterochromatin dysregulation induces translocation of nuclear materials into cytoplasm, which is important for inflammatory diseases and cancer.

In eukaryote cells, core components of chromatin, such as histones and DNA, are packaged in nucleus. Leakage of nuclear materials into cytosol will induce pathological effects. However, the underlying mechanisms remain elusive. Here, cytoplasmic localization of nuclear materials induced by chromatin dysregulation (CLIC) in mammalian cells is reported. H3K9me3 inhibition by small chemicals, HP1α knockdown, or knockout of H3K9 methylase SETDB1, induces formation of cytoplasmic puncta containing histones H3.1, H4 and cytosolic DNA, which in turn activates inflammatory genes and autophagic degradation. Autophagy deficiency rescues H3 degradation, and enhances the activation of inflammatory genes. MRE11, a subunit of MRN complex, enters cytoplasm after heterochromatin dysregulation. Deficiency of MRE11 or NBS1, but not RAD50, inhibits CLIC puncta in cytosol. MRE11 depletion represses tumor growth enhanced by HP1α deficiency, suggesting a connection between CLIC and tumorigenesis. This study reveals a novel pathway that heterochromatin dysregulation induces translocation of nuclear materials into cytoplasm, which is important for inflammatory diseases and cancer. [ABSTRACT FROM AUTHOR]

Forming tight interaction with both Purkinje and granule cells (GCs), Bergmann glia (BG) are essential for cerebellar morphogenesis and neuronal homeostasis. However, how BG act in this process is unclear without comprehensive transcriptome landscape of BG. Here, high temporal‐resolution investigation of transcriptomes with FACS‐sorted BG revealed the dynamic expression of genes within given functions and pathways enabled BG to assist neural migration and construct neuron‐glia network. It is found that the peak time of GCs migration (P7‐10) strikingly coincides with the downregulation of extracellular matrix (ECM) related genes, and the disruption of which by Setdb1 ablation at P7‐10 in BG leads to significant migration defect of GCs emphasizing the criticality of Nfix‐Setdb1 mediated H3K9me3 repressive complex for the precise regulation of GCs migration in vivo. Thus, BG's transcriptomic landscapes offer an insight into the mechanism by which BG are in depth integrated in cerebellar neural network. [ABSTRACT FROM AUTHOR]