The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate.

Heterochromatic loci marked by histone H3 lysine 9 dimethylation (H3K9me2) are enriched at the nuclear periphery in metazoans, but the effect of spatial position on heterochromatin function has not been defined. Here, we remove three nuclear lamins and lamin B receptor (LBR) in mouse embryonic stem cells (mESCs) and show that heterochromatin detaches from the nuclear periphery. Mutant mESCs sustain naïve pluripotency and maintain H3K9me2 across the genome but cannot repress H3K9me2-marked genes or transposons. Further, mutant cells fail to differentiate into epiblast-like cells (EpiLCs), a transition that requires the expansion of H3K9me2 across the genome. Mutant EpiLCs can silence naïve pluripotency genes and activate epiblast-stage genes. However, H3K9me2 cannot repress markers of alternative fates, including primitive endoderm. We conclude that the nuclear periphery controls the spatial position, dynamic remodeling, and repressive capacity of H3K9me2-marked heterochromatin to shape cell fate decisions.

Muscle functions as a connective tissue and source of extracellular matrix in planarians.

Regeneration and tissue turnover require new cell production and positional information. Planarians are flatworms capable of regenerating all body parts using a population of stem cells called neoblasts. The positional information required for tissue patterning is primarily harbored by muscle cells, which also control body contraction. Here we produce an in silico planarian matrisome and use recent whole-animal single-cell-transcriptome data to determine that muscle is a major source of extracellular matrix (ECM). No other ECM-secreting, fibroblast-like cell type was detected. Instead, muscle cells express core ECM components, including all 19 collagen-encoding genes. Inhibition of muscle-expressed hemicentin-1 (hmcn-1), which encodes a highly conserved ECM glycoprotein, results in ectopic peripheral localization of cells, including neoblasts, outside of the muscle layer. ECM secretion and hmcn-1-dependent maintenance of tissue separation indicate that muscle functions as a planarian connective tissue, raising the possibility of broad roles for connective tissue in adult positional information.

OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development.

TET enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine and higher oxidized derivatives. TETs stably associate with and are post-translationally modified by the nutrient-sensing enzyme OGT, suggesting a connection between metabolism and the epigenome. Here, we show for the first time that modification by OGT enhances TET1 activity in vitro. We identify a TET1 domain that is necessary and sufficient for binding to OGT and report a point mutation that disrupts the TET1-OGT interaction. We show that this interaction is necessary for TET1 to rescue hematopoetic stem cell production in tet mutant zebrafish embryos, suggesting that OGT promotes TET1's function during development. Finally, we show that disrupting the TET1-OGT interaction in mouse embryonic stem cells changes the abundance of TET2 and 5-methylcytosine, which is accompanied by alterations in gene expression. These results link metabolism and epigenetic control, which may be relevant to the developmental and disease processes regulated by these two enzymes.