Highlights d SAFB maintains higher-order organization of pericentromeric heterochromatin d SAFB interacts with repeat element RNAs such as MajSAT d SAFB drives phase separation that is promoted by MajSAT RNAs d Depletion of SAFB leads to a remodeling of 3D genome organization

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In the nucleus, chromatin is folded into hierarchical architecture that is tightly linked to various nuclear functions. However, the underlying molecular mechanisms that confer these architectures remain incompletely understood. Here, we investigated the functional roles of H3 lysine 9 dimethylation (H3K9me2), one of the abundant histone modifications, in three-dimensional (3D) genome organization. Unlike in mouse embryonic stem cells, inhibition of methyltransferases G9a and GLP in differentiated cells eliminated H3K9me2 predominantly at A-type (active) genomic compartments, and the level of residual H3K9me2 modifications was strongly associated with B-type (inactive) genomic compartments. Furthermore, chemical inhibition of G9a/GLP in mouse hepatocytes led to decreased chromatin-nuclear lamina interactions mainly at G9a/GLP-sensitive regions, increased degree of genomic compartmentalization, and up-regulation of hundreds of genes that were associated with alterations of the 3D chromatin. Collectively, our data demonstrated essential roles of H3K9me2 in 3D genome organization.

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Background Injury induces profound transcriptional remodeling events, which could lead to only wound healing, partial tissue repair, or perfect regeneration in different species. Injury-responsive enhancers (IREs) are cis-regulatory elements activated in response to injury signals, and have been demonstrated to promote tissue regeneration in some organisms such as zebrafish and flies. However, the functional significances of IREs in mammals remain elusive. Moreover, whether the transcriptional responses elicited by IREs upon injury are conserved or specialized in different species, and what sequence features may underlie the functional variations of IREs have not been elucidated. Results We identified a set of IREs that are activated in both regenerative and non-regenerative neonatal mouse hearts upon myocardial ischemia-induced damage by integrative epigenomic and transcriptomic analyses. Motif enrichment analysis showed that AP-1 and ETS transcription factor binding motifs are significantly enriched in both zebrafish and mouse IREs. However, the IRE-associated genes vary considerably between the two species. We further found that the IRE-related sequences in zebrafish and mice diverge greatly, with the loss of IRE inducibility accompanied by a reduction in AP-1 and ETS motif frequencies. The functional turnover of IREs between zebrafish and mice is correlated with changes in transcriptional responses of the IRE-associated genes upon injury. Using mouse cardiomyocytes as a model, we demonstrated that the reduction in AP-1 or ETS motif frequency attenuates the activation of IREs in response to hypoxia-induced damage. Conclusions By performing comparative genomics analyses on IREs, we demonstrated that inter-species variations in AP-1 and ETS motifs may play an important role in defining the functions of enhancers during injury response. Our findings provide important insights for understanding the molecular mechanisms of transcriptional remodeling in response to injury across species.

In the nucleus, chromatin is folded into hierarchical architecture that is tightly linked to various nuclear functions. However, the underlying molecular mechanisms that confer these architectures remain incompletely understood. Here, we investigated the functional roles of H3 lysine 9 dimethylation (H3K9me2), one of the abundant histone modifications, in three-dimensional (3D) genome organization. Unlike mouse embryonic stem cells (mESCs), inhibition of methyltransferases G9a and GLP in differentiated cells eliminated H3K9me2 predominantly at A-type (active) genomic compartments, and the level of residual H3K9me2 modification was strongly associated with genomic compartments in differentiated cells. Furthermore, chemical inhibition of G9a/GLP in mouse hepatocytes led to the decreased chromatin-nuclear lamina interactions mainly at G9a/GLP sensitive regions (GSRs), the increased degree of genomic compartmentalization, and the up-regulation of hundreds of genes that were associated with alterations of the 3D chromatin. Collectively, our data demonstrated essential roles of H3K9me2 in 3D genome organization.