Abstract treeclimbR is for analyzing hierarchical trees of entities, such as phylogenies or cell types, at different resolutions. It proposes multiple candidates that capture the latent signal and pinpoints branches or leaves that contain features of interest, in a data-driven way. It outperforms currently available methods on synthetic data, and we highlight the approach on various applications, including microbiome and microRNA surveys as well as single-cell cytometry and RNA-seq datasets. With the emergence of various multi-resolution genomic datasets, treeclimbR provides a thorough inspection on entities across resolutions and gives additional flexibility to uncover biological associations.
Abstract The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature, and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1-/- mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1-/- mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1, and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.
Abstract Symmetrical 7q11.23 dosage alterations cause craniofacial and cognitive/behavioral phenotypes that provide a privileged entry point into the evolution of the modern human face and (pro-) sociality. We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 Copy Number Variants (CNVs). Our results reveal a key contribution of BAZ1B to NCSC in vitro induction and migration, coupled with a crucial involvement in neural crest (NC)-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we uncover a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face. One Sentence Summary BAZ1B dosage shapes the modern human face.
In biology, inheritance is a process that ensures the transfer of features and traits from parent to offspring. The most classic view of parental inheritance is that it is genetic and is embedded in genes contained in the genome in germ cells. However, genetic inheritance is now known to contribute to only a part of what an individual can transmit to its progeny. Thus, further to innate traits that each individual receives from its parents, acquired traits, which are traits acquired upon exposure to environmental factors or personal experiences, can also be inherited. This form of inheritance is not encoded in the sequence of genes but is mediated by mechanisms and processes elicited by the environment that modify the activity of the genome persistently across generations. Because it is not encoded in DNA sequences, it is called epigenetic or non-genetic. These mechanisms establish a link between the genome and the environment. They relate to the extremely important question of nature versus nurture namely, how much our own make-up is genetically or epigenetically determined, a question that remains unresolved. In August 2017, an international symposium was organized in Zurich, Switzerland to address the question of epigenetic inheritance.
The Latsis symposium 2017 on “Transgenerational epigenetic inheritance: from biology to society” held at the ETH Zurich gathered international leaders in the field and focused on major questions and current challenges raised by the concept of epigenetic inheritance. The symposium was one of the first fully dedicated to the theme of epigenetic inheritance and covered scientific aspects from invertebrates to humans, and from behavior to metabolism in humans and animal models, mental health and epidemiology, bioinformatics and ethics. The symposium lasted 2.5 days and was attended by about 150 people from different countries. The program was structured in sessions of 3–3 h 30 min each (total of five sessions) including invited talks and short oral presentations. This summary provides an overview of the speakers’ presentations and focuses on four major topics: (i) evidence and challenges for epigenetic inheritance in humans, (ii) new insight and major questions raised by work in animal models, (iii) methodologies in epigenetics and (iv) evolution, societal impact and broader considerations.
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