Revealing the function of heterochromatin spatial organization in response to early-life environmental challenges in C. elegans

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The spatial distribution of transcriptionally active euchromatin and repressed heterochromatin is not random and enables a functional compartmentalization of the genome. In particular, silent heterochromatin is actively sequestered at the nuclear periphery, while active euchromatin is centrally located. Yet, the function of 3D chromatin distribution per se remains largely unknown, mainly due to the inability to selectively perturb chromatin spatial organization while leaving other nuclear processes unaltered. In this proposal, we will take advantage of the roundworm C. elegans, the only organism where a highly specific perinuclear anchor of heterochromatin, termed CEC-4, was identified to date, to impair heterochromatin spatial distribution globally and unravel the consequences for tissue integrity and organismal health. Despite a genome-wide impairment of spatial genome positioning, ablating cec-4 does not alter transcription globally and cec-4 mutants display no phenotype under optimal growth conditions unless challenged with an ectopic transcriptional stimulus. This raises the fascinating possibility that the spatial compartmentalization of chromatin is functional in coordinating the transcriptional response to non-programmed cues. Intriguingly, animals growing in their natural context are constantly exposed to environmental stresses, which induce profound gene expression changes. However, how environmental cues affects the spatial organization of the genome and whether this critically contributes to the stress response is currently unknown. Our preliminary data suggest that an accurate spatial segregation of euchromatin and heterochromatin is indeed functional when animals are exposed to environmental stress. In this proposal, we plan to characterize the functional interaction between the environment and 3D chromatin organization further. In particular, we will expose cec-4 mutants and wt animals to environmental stress and measure i) genome-nuclear lamina interactions, ii) chromatin accessibility and iii) gene expression, during stress and upon recovery in two different tissues, allowing us to determine how different cell types within an organism respond to the same environmental cue. Interestingly, in several species an early life stress exposure can influence events that occur later in life, with mechanisms that remain largely unknown. In this work, we will identify genes de-regulated during the stress response when heterochromatin spatial distribution is impaired and determine their impact on development and aging later in life, upon restoration of optimal growth conditions. To achieve our goals, my team will employ a combination of microscopy, molecular and genetic approaches. Because all organisms, including humans, are constantly exposed to a changing environment, the implications of this study are likely to be vast.