Much progress has been achieved in disentangling evolutionary relationships among species in the tree of life, but some taxonomic groups remain difficult to resolve despite increasing availability of genome-scale data sets. Here we present a practical approach to studying ancient divergences in the face of high levels of conflict, based on explicit gene genealogy interrogation (GGI). We show its efficacy in resolving the controversial relationships within the largest freshwater fish radiation (Otophysi) based on newly generated DNA sequences for 1,051 loci from 225 species. Initial results using a suite of standard methodologies revealed conflicting phylogenetic signal, which supports ten alternative evolutionary histories among early otophysan lineages. By contrast, GGI revealed that the vast majority of gene genealogies supports a single tree topology grounded on morphology that was not obtained by previous molecular studies. We also reanalysed published data sets for exemplary groups with recalcitrant resolution to assess the power of this approach. GGI supports the notion that ctenophores are the earliest-branching animal lineage, and adds insight into relationships within clades of yeasts, birds and mammals. GGI opens up a promising avenue to account for incompatible signals in large data sets and to discern between estimation error and actual biological conflict explaining gene tree discordance.

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia.

SUMMARY The Polycomb Repressive Complex 2 (PRC2) methylates lysine 27 of histone H3 (H3K27) through its catalytic subunit Ezh2. PRC2-mediated di- and tri-methylation (H3K27me2/me3) have been interchangeably associated with gene repression. However, it remains unclear whether these two degrees of H3K27 methylation have different functions. In this study, we have generated isogenic mouse embryonic stem cells (ESCs) with a modified H3K27me2/H3K27me3 ratio. Our findings document dynamic developmental control in the genomic distribution of H3K27me2 and H3K27me3 at regulatory regions in ESCs. They also reveal that modifying the ratio of H3K27me2 and H3K27me3 is sufficient for the acquisition and repression of defined cell lineage transcriptional programs and phenotypes, along with influencing induction of the ESC ground state.