The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers.

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TGFβ signalling in context.

Transposable elements (TEs) are widely known for their deleterious consequences of selfish propagation and mutagenesis. However, as described in this Review, TEs also provide hosts with rich, beneficial gene-regulatory machinery in the form of regulatory DNA elements and TE-derived gene products. The authors highlight the diverse regulatory contributions of TEs to organismal physiology and pathology, provide a framework for responsibly assigning functional roles to TEs and offer visions for the future.

Regulatory activities of transposable elements: from conflicts to benefits.

Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.

Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development

Histone modifications and chromatin-associated protein complexes are crucially involved in the control of gene expression, supervising cell fate decisions and differentiation. Many promoters in embryonic stem (ES) cells harbor a distinctive histone modification signature that combines the activating histone H3 Lys 4 trimethylation (H3K4me3) mark and the repressive H3K27me3 mark. These bivalent domains are considered to poise expression of developmental genes, allowing timely activation while maintaining repression in the absence of differentiation signals. Recent advances shed light on the establishment and function of bivalent domains; however, their role in development remains controversial, not least because suitable genetic models to probe their function in developing organisms are missing. Here, we explore avenues to and from bivalency and propose that bivalent domains and associated chromatin-modifying complexes safeguard proper and robust differentiation.

/pdf/a-double-take-on-bivalent-promoters-3cqun7g04k.pdf

A double take on bivalent promoters

Transposable elements (TEs) are major components of eukaryotic genomes. However, the extent of their impact on genome evolution, function, and disease remain a matter of intense interrogation. The rise of genomics and large-scale functional assays has shed new light on the multi-faceted activities of TEs and implies that they should no longer be marginalized. Here, we introduce the fundamental properties of TEs and their complex interactions with their cellular environment, which are crucial to understanding their impact and manifold consequences for organismal biology. While we draw examples primarily from mammalian systems, the core concepts outlined here are relevant to a broad range of organisms.

https://link.springer.com/content/pdf/10.1186/s13059-018-1577-z.pdf

Ten things you should know about transposable elements

Endogenous retroviruses (ERVs) are abundant in mammalian genomes and contain sequences modulating transcription. The impact of ERV propagation on the evolution of gene regulation remains poorly understood. We found that ERVs have shaped the evolution of a transcriptional network underlying the interferon (IFN) response, a major branch of innate immunity, and that lineage-specific ERVs have dispersed numerous IFN-inducible enhancers independently in diverse mammalian genomes. CRISPR-Cas9 deletion of a subset of these ERV elements in the human genome impaired expression of adjacent IFN-induced genes and revealed their involvement in the regulation of essential immune functions, including activation of the AIM2 inflammasome. Although these regulatory sequences likely arose in ancient viruses, they now constitute a dynamic reservoir of IFN-inducible enhancers fueling genetic innovation in mammalian immune defenses.

http://science.sciencemag.org/content/sci/351/6277/1083.full.pdf

Regulatory evolution of innate immunity through co-option of endogenous retroviruses

The mammalian placenta is remarkably distinct between species, suggesting a history of rapid evolutionary diversification. To gain insight into the molecular drivers of placental evolution, we compared biochemically predicted enhancers in mouse and rat trophoblast stem cells (TSCs) and found that species-specific enhancers are highly enriched for endogenous retroviruses (ERVs) on a genome-wide level. One of these ERV families, RLTR13D5, contributes hundreds of mouse-specific histone H3 lysine 4 monomethylation (H3K4me1)- and histone H3 lysine 27 acetylation (H3K27ac)-defined enhancers that functionally bind Cdx2, Eomes and Elf5-core factors that define the TSC regulatory network. Furthermore, we show that RLTR13D5 is capable of driving gene expression in rat placental cells. Analysis in other tissues shows that species-specific ERV enhancer activity is generally restricted to hypomethylated tissues, suggesting that tissues permissive for ERV activity gain access to an otherwise silenced source of regulatory variation. Overall, our results implicate ERV enhancer co-option as a mechanism underlying the extensive evolutionary diversification of placental development.

/pdf/endogenous-retroviruses-function-as-species-specific-2hnb0aqjx5.pdf

Endogenous retroviruses function as species-specific enhancer elements in the placenta

Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs

The mammalian placenta exhibits elevated expression of endogenous retroviruses (ERVs), but the evolutionary significance of this feature remains unclear I propose that ERV-mediated regulatory evolution was, and continues to be, an important mechanism underlying the evolution of placental development Many recent studies have focused on the co-option of ERV-derived genes for specific functional adaptations in the placenta However, the co-option of ERV-derived regulatory elements could potentially lead to the incorporation of entire gene regulatory networks, which, I argue, would facilitate relatively rapid developmental evolution of the placenta I suggest a model in which an ancient retroviral infection led to the establishment of the ancestral placental developmental gene network through the co-option of ERV-derived regulatory elements Consequently, placental development would require elevated tolerance to ERV activity This in turn would expose a continuous stream of novel ERV mutations that may have catalyzed the developmental diversification of the mammalian placenta

/pdf/retroviruses-facilitate-the-rapid-evolution-of-the-mammalian-iysz8dey6f.pdf

Edward B. Chuong

Papers

Regulatory activities of transposable elements: from conflicts to benefits.

Regulatory evolution of innate immunity through co-option of endogenous retroviruses

Endogenous retroviruses function as species-specific enhancer elements in the placenta

Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs

Retroviruses facilitate the rapid evolution of the mammalian placenta