Postdoctoral Associate, Yale Univeristy
Study early human neuronal differentiation process focusing on role of lncRNAs in disease
We are developing mini-brains in vitro (so called neuronal organoids), by using human induced pluripotent stem cells' derived from donor's fibroblasts (control and/or patient). iPSCs are very "young" and able to generate all kind of cell types of our entire body. The specific fate, is determined by specific factors and culture condition. We use the right one to drive them into neuronal fate, in particular to generate a population of neurons that mostly constitute the cortex of human brain. In this way we have the ability to mimics in a dish the early processes of neuronal development that otherwise would be impossible to follow because of human brain’s complexity and limitations of functional studies. These organoids, resemble a piece of tissue, so it's very intriguing to study how cell to cell interact and how they coordinate themself to generate an organized "brain" in vitro. In particular, I'm interesting to use the organoids tool, to elucidated the function of many lncRNA, these emerging non coding RNA that occupied the majority of our trasncriptome. The DNA is still the core of knowledge in a cell but protein and RNA, in particular non coding RNA are becoming more and more key players in orchestrate the complicated process of life. One of my main goal is to first identify, lncRNAs specifically expressed in the brain and perturbing their expression profile, study their function in the in vitro model of organoids, looking at proliferation, neuronal differentiation and other parameters that I can measure by quantitative assays.
Abstract: Autism spectrum disorder (ASD) is more prevalent in males, and the mechanisms behind this sex-differential risk are not fully understood. Two competing, but not mutually exclusive, hypotheses are that ASD risk genes are sex-differentially regulated, or alternatively, that they interact with characteristic sexually dimorphic pathways. Here we characterized sexually dimorphic gene expression in multiple data sets from neurotypical adult and prenatal human neocortical tissue, and evaluated ASD risk genes for evidence of sex-biased expression. We find no evidence for systematic sex-differential expression of ASD risk genes. Instead, we observe that genes expressed at higher levels in males are significantly enriched for genes upregulated in post-mortem autistic brain, including astrocyte and microglia markers. This suggests that it is not sex-differential regulation of ASD risk genes, but rather naturally occurring sexually dimorphic processes, potentially including neuron–glial interactions, that modulate the impact of risk variants and contribute to the sex-skewed prevalence of ASD.
Pub.: 19 Feb '16, Pinned: 29 Jun '17
Abstract: Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood1, 2, 3. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge4, 5, 6, 7, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.
Pub.: 05 Dec '16, Pinned: 29 Jun '17
Abstract: The function of most human long noncoding RNAs (lncRNAs) remains unclear. Our studies identified a highly up-regulated mammalian lncRNA, FOXD3-AS1, known as linc1623 in mouse, in the setting of hyperoxia/reactive oxygen species (ROS)-induced lung injury. We found that ROS induced a robust expression of FOXD3-AS1 in mouse lung tissue. Functionally, FOXD3-AS1 promoted oxidative stress-induced lung epithelial cell death. In human lung epithelial cells, the microRNA-150 (miR-150) was identified to interact with FOXD3-AS1; this finding was confirmed using the luciferase reporter assays. Consistently, mutation on the miR-150 pairing sequence in FOXD3-AS1 abolished the interactions between FOXD3-AS1 and miR-150. Additionally, miR-150 mimics suppressed the level of FOXD3-AS1. The antisense oligos of FOXD3-AS1 significantly augmented the intracellular level of miR-150, supporting the theory of sponging effects of FOXD3-AS1 on miR-150. We further investigated the cellular function of miR-150 in our lung injury models. miR-150 conferred a cyto-protective role in lung epithelial cells after oxidative stress, whereas FOXD3-AS1 promoted cell death. Taken together, our studies indicated that FOXD3-AS1 serves as a sponge or as a competing endogenous noncoding RNA for miR-150, restricting its capability to promote cell growth and thereby exaggerating hyperoxia-induced lung epithelial cell death.-Zhang, D., Lee, H., Haspel, J. A., Jin, Y. Long noncoding RNA FOXD3-AS1 regulates oxidative stress-induced apoptosis via sponging microRNA-150.
Pub.: 29 Jun '17, Pinned: 29 Jun '17
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