Project description:We carried out cell-type specific whole genome bisulfite sequencing from primate brains (orthologous region to human BA46) that underwent fluorescence-activated nuclei sorting (FANS).
Project description:A fundamental challenge in molecular biology is to understand how evolving genomes can acquire new functions. Several recent studies have underscored how non-conserved sequences can contribute to organismal diversification in the primate lineage. Actively transcribed, non-coding parts of the genome provide a potential platform for the development of new functional sequences, but their biological and evolutionary roles remain largely unexplored. Here we show that a set of neutrally evolving long non-coding RNAs (lncRNA) arising from small nucleolar RNA Host Genes (SNHGs) are highly expressed in skin and dysregulated in inflammatory conditions. Using SNHG7 and human epidermal keratinocytes as a model, we describe a mechanism by which these lncRNAs can increase self-renewal and inhibit differentiation. SNHG7 lncRNA’s activity has been acquired recently in the primate lineage and depends on a short sequence required for microRNA binding. Taken together, our results highlight the importance of understanding the role of fast-evolving transcripts in normal and diseased epithelia, and show how poorly conserved, actively transcribed non-coding sequences can participate in the evolution of genomic functionality.
Project description:Primary objectives: The primary objective is to investigate circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
Primary endpoints: circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
Project description:The human genome harbors 15,000 pseudogenes, except very few can transcribe non-coding RNAs or encode truncated proteins, a large number of which without transcriptional capacity are functionally unknown. Here, we proposed and verified that pseudogene DNA sequences can form chromatin contacts that act as anchors of chromatin loops and boundaries of topologically associating domains (TADs). More amazing, due to the sequence-specificity of pseudogenes, TAD boundaries containing them in the human genome were primarily species-specific, including human-specific and primate-specific ones. We found that during primate evolution, by inheritance from parent genes, certain pseudogenes can introduce additional transcription factor-binding sequences, especially CTCF, at their insertion sites to generate species-specific TAD boundaries, and due to the participation in TAD evolution, CTCF binding motifs on pseudogenes were subjected to significantly heightened selection pressure. Deleting these pseudogenes in human embryonic stem cells (hESCs) disrupted the structure of species-specific TADs, whereas inserting them in mouse embryonic stem cells (mESCs) mediated new TADs formation, and pseudogenes involved in three-dimensional (3D) genome formation were critical for maintaining hESCs self-renewal. The structural necessity and biological function of these pseudogenes demonstrated the broad significance of pseudogenes in 3D genome construction and evolution.