Suv39h-catalysed H3K9me3 is critical for euchromatic genome organisation and the maintenance of gene transcription

Abstract

H3K9me3-dependent heterochromatin is critical for the silencing of repeat-rich pericentromeric regions and also has key roles in repressing lineage-inappropriate protein-coding genes in differentiation and development. Here, we investigate the molecular consequences of heterochromatin loss in cells deficient in both Suv39h1 and Suv39h2 (Suv39DKO), the major mammalian histone methyltransferase enzymes that catalyse heterochromatic H3K9me3 deposition. Unexpectedly, we reveal a predominant repression of protein-coding genes in Suv39DKO cells, with these differentially expressed genes principally in euchromatic (DNaseI-accessible, H3K27ac-marked) rather than heterochromatic (H3K9me3-marked) regions. Examination of the 3D nucleome reveals that transcriptomic dysregulation occurs in euchromatic regions close to the nuclear periphery in 3-dimensional space. Moreover, this transcriptomic dysregulation is highly correlated with altered 3-dimensional genome organization in Suv39DKO cells. Together, our results suggest that the nuclear lamina-tethering of Suv39-dependent H3K9me3 domains provides an essential scaffold to support euchromatic genome organisation and the maintenance of gene transcription for healthy cellular function.

Chromosomes distribute randomly to, but not within, human neutrophil nuclear lobes

“…It has been proposed that the organization could be due to the differential timing of centromere separation ( Gerlich et al., 2003 ) or chromosome position during mitosis ( Bolzer et al., 2005 ), differential interaction between chromosomes and the nuclear periphery and/or other nuclear bodies ( Cremer and Cremer, 2001 ) or simply the force of transcription from highly transcribed chromosomes acting on those lowly transcribed ( Yin et al., 1995 ). A number of purposes for the radial organization have also been proposed, from protecting the genome from viruses and mutagens using a layer of highly repetitive and heterochromatic DNA ( Hsu, 1975 ) to providing nuclear stability or rigidity ( Bolzer et al., 2005 ; Nava et al., 2020 ; Keenan et al., 2020 ). Given our findings in the highly malleable neutrophil nuclei the latter seems unlikely.…”

Heterochromatin and Polycomb as regulators of haematopoiesis

“…An additional dimension in heterochromatin regulation of haematopoiesis is the biophysical link between heterochromatin and the nuclear lamina which is thought to provide structural support to the nucleus and to protect the genome from damage. Our recent studies suggest the stability of heterochromatin at the nuclear periphery also has an important gene regulatory function supporting gene transcription in euchromatic regions [ 31 ], and that this peripheral localisation of heterochromatin may also guide the three-dimensional positioning of chromosomes into multi-lobed neutrophil nuclei [ 32 ]. Interestingly, a recent study has shown that the nuclei of HSCs undergo dramatic morphological changes during myeloid or lymphoid differentiation [ 33 ].…”