Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions.

Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcriptionally silent regions of the genome. These neogenes (NGs) are virtually undetectable in large collections of normal tissues or non-EwS tumors and can be silenced by CRISPR interference at regulatory EWS::FLI1-bound microsatellites. Ribosome profiling and proteomics further show that some NGs are translated into highly EwS-specific peptides. More generally, we show that hundreds of NGs can be detected in diverse cancers characterized by chimeric TFs. Altogether, this study identifies the transcription, processing, and translation of novel, specific, highly expressed multi-exonic transcripts from otherwise silent regions of the genome as a new activity of aberrant TFs in cancer.

Interactions between U and V sex chromosomes during the life cycle of Ectocarpus.

In many animals and flowering plants, sex determination occurs in the diploid phase of the life cycle with XX/XY or ZW/ZZ sex chromosomes. However, in early diverging plants and most macroalgae, sex is determined by female (U) or male (V) sex chromosomes in a haploid phase called the gametophyte. Once the U and V chromosomes unite at fertilization to produce a diploid sporophyte, sex determination no longer occurs, raising key questions about the fate of the U and V sex chromosomes in the sporophyte phase. Here, we investigate genetic and molecular interactions of the UV sex chromosomes in both the haploid and diploid phases of the brown alga Ectocarpus. We reveal extensive developmental regulation of sex chromosome genes across its life cycle and implicate the TALE-HD transcription factor OUROBOROS in suppressing sex determination in the diploid phase. Small RNAs may also play a role in the repression of a female sex-linked gene, and transition to the diploid sporophyte coincides with major reconfiguration of histone H3K79me2, suggesting a more intricate role for this histone mark in Ectocarpus development than previously appreciated.

The epigenetic origin of life history transitions in plants and algae.

Plants and algae have a complex life history that transitions between distinct life forms called the sporophyte and the gametophyte. This phenomenon-called the alternation of generations-has fascinated botanists and phycologists for over 170 years. Despite the mesmerizing array of life histories described in plants and algae, we are only now beginning to learn about the molecular mechanisms controlling them and how they evolved. Epigenetic silencing plays an essential role in regulating gene expression during multicellular development in eukaryotes, raising questions about its impact on the life history strategy of plants and algae. Here, we trace the origin and function of epigenetic mechanisms across the plant kingdom, from unicellular green algae through to angiosperms, and attempt to reconstruct the evolutionary steps that influenced life history transitions during plant evolution. Central to this evolutionary scenario is the adaption of epigenetic silencing from a mechanism of genome defense to the repression and control of alternating generations. We extend our discussion beyond the green lineage and highlight the peculiar case of the brown algae. Unlike their unicellular diatom relatives, brown algae lack epigenetic silencing pathways common to animals and plants yet display complex life histories, hinting at the emergence of novel life history controls during stramenopile evolution.