Extreme disruption of heterochromatin is required for accelerated haematopoietic aging.

Loss of heterochromatin has been proposed as a universal mechanism of aging across different species and cell-types. However, a comprehensive analysis of haematopoietic changes caused by heterochromatin loss is lacking. Moreover, there is conflict in the literature around the role of the major heterochromatic histone methyltransferase Suv39h1 in the aging process. Here, we use individual and dual deletion of Suv39h1 and Suv39h2 enzymes to examine the causal role of heterochromatin loss in haematopoietic cell development. Loss of neither Suv39h1 nor Suv39h2 individually had any effect on haematopoietic stem cell function or the development of mature lymphoid or myeloid lineages. However, deletion of both enzymes resulted in characteristic changes associated with aging such as reduced haematopoietic stem cell (HSC) function, thymic involution and decreased lymphoid output with a skewing towards myeloid development, and increased memory T cells at the expense of naive T cells. These cellular changes were accompanied with molecular changes consistent with aging including alterations in nuclear shape and increased nucleolar size. Together, our results indicate that the haematopoietic system has a remarkable tolerance for major disruptions in chromatin structure and reveal a role for Suv39h2 in depositing sufficient H3K9me3 to protect the entire haematopoietic system from changes associated with premature aging.