Epigenetics Polycystic ovary syndrome (PCOS) is a major cause of female infertility. It is characterized by hormonal and often metabolic dysfunction but little is understood about its etiology. For women with PCOS who do become pregnant, there is a high probability that their daughters will develop PCOS. This heritability has been proposed to arise, at least partially, if the embryos are exposed to abnormal levels of hormones. Mimouni et al. studied a mouse model of PCOS and found several differentially methylated genes in the ovaries of third-generation mice, indicating epigenetic-mediated heritability. Several of these genes were also differentially methylated in blood samples from mothers and daughters with PCOS, indicating the potential for methylation as a diagnostic biomarker. Cell Metab. 10.1016/j.cmet.2021.01.004 (2021).
The brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders. The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain. Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes including MEF2C, SATB2, and TCF4, with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity. We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease.
We intuitively know that our personalities and temperaments -- whether we're introverts or extroverts, how we respond to novelty or adversity, whether we're hard-driving or laid back -- are the result of a complex interaction of nature and nurture. We likely start with some general social tendencies established by genes inherited from our parents. But it seems equally evident that experience matters. Did you grow up beloved or neglected? Have your surroundings and people close to you encouraged confident exploration or grim self-protection?
We constructed maps of allelic imbalances in DNA methylation, histone marks, and gene transcription in 71 epigenomes from 36 distinct cell and tissue types from 13 donors. Deep (1691-fold) combined WGBS read coverage across 49 methylomes revealed CpG methylation imbalances exceeding 30% differences at 5% of the loci, which is more conservative than previous estimates in the 8 to 10% range; a similar value (8%) is observed in our dataset when we lowered our threshold for detecting allelic imbalance to 20% methylation difference between the two alleles. Extensive sequence-dependent CpG methylation imbalances were observed at thousands of heterozygous regulatory loci. Stochastic switching, defined as random transitions between fully methylated and unmethylated states of DNA, occurred at thousands of regulatory loci bound by transcription factors (TFs). Our results explain the conservation of intermediate methylation states at regulatory loci by showing that the intermediate methylation reflects the relative frequencies of fully methylated and fully unmethylated epialleles.
Johann Wolfgang von Goethe, the 18th-century poet and philosopher, believed life was hardwired with archetypes, or models, which instructed its development. Yet he was fascinated with how life could, at the same time, be so malleable. One day, while meditating on a leaf, the poet had what you might call a proto-evolutionary thought: Plants were never created "and then locked into the given form" but have instead been given, he later wrote, a "felicitous mobility and plasticity that allows them to grow and adapt themselves to many different conditions in many different places." A rediscovery of principles of genetic inheritance in the early 20th century showed that organisms could not learn or acquire heritable traits by interacting with their environment, but they did not yet explain how life could undergo such shapeshifting tricks--the plasticity that fascinated Goethe. A polymathic and pioneering British biologist proposed such a mechanism for how organisms could adapt to their environment, upending the early field of evolutionary biology.