Archaeological mitogenomes illuminate the historical ecology of sea otters (Enhydra lutris) and the viability of reintroduction.

Genetic analyses are an important contribution to wildlife reintroductions, particularly in the modern context of extirpations and ecological destruction. To address the complex historical ecology of the sea otter (Enhydra lutris) and its failed 1970s reintroduction to coastal Oregon, we compared mitochondrial genomes of pre-extirpation Oregon sea otters to extant and historical populations across the range. We sequenced, to our knowledge, the first complete ancient mitogenomes from archaeological Oregon sea otter dentine and historical sea otter dental calculus. Archaeological Oregon sea otters (n = 20) represent 10 haplotypes, which cluster with haplotypes from Alaska, Washington and British Columbia, and exhibit a clear division from California haplotypes. Our results suggest that extant northern populations are appropriate for future reintroduction efforts. This project demonstrates the feasibility of mitogenome capture and sequencing from non-human dental calculus and the diverse applications of ancient DNA analyses to pressing ecological and conservation topics and the management of at-risk/extirpated species.

HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma.

Gain-of-function mutations in the catalytic site of EZH2 (Enhancer of Zeste Homologue 2), is observed in about 22% of diffuse large B-cell lymphoma (DLBCL) cases. Here we show that selective inhibition of histone deacetylase 1,2 (HDAC1,2) activity using a small molecule inhibitor causes cytotoxic or cytostatic effects in EZH2 gain-of-function mutant (EZH2GOF) DLBCL cells. Our results show that blocking the activity of HDAC1,2 increases global H3K27ac without causing a concomitant global decrease in H3K27me3 levels. Our data shows that inhibition of HDAC1,2 is sufficient to decrease H3K27me3 present at DSBs, decrease DSB repair and activate the DNA damage response in these cells. In addition to increased H3K27me3, we found that the EZH2GOF DLBCL cells overexpress another chemotherapy resistance factor - B-lymphoma and BAL-associated protein (BBAP). BBAP monoubiquitinates histone H4K91, a residue that is also subjected to acetylation. Our results show that selective inhibition of HDAC1,2 increases H4K91ac, decreases BBAP-mediated H4K91 monoubiquitination, impairs BBAP-dependent DSB repair and sensitizes the refractory EZH2GOF DLBCL cells to treatment with doxorubicin, a chemotherapy agent. Hence, selective HDAC1,2 inhibition provides a novel DNA repair mechanism-based therapeutic approach as it can overcome both EZH2- and BBAP-mediated DSB repair in the EZH2GOF DLBCL cells.