Mapping the developmental trajectory of human astrocytes reveals divergence in glioblastoma.

Glioblastoma (GBM) is defined by heterogeneous and resilient cell populations that closely reflect neurodevelopmental cell types. Although it is clear that GBM echoes early and immature cell states, identifying the specific developmental programmes disrupted in these tumours has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM.

Epigenetic remodeling and 3D chromatin reorganization governed by NKX2-1 drive neuroendocrine prostate cancer.

A significant number of castration-resistant prostate cancer (CRPC) evolve into a neuroendocrine (NE) subtype termed NEPC, leading to resistance to androgen receptor (AR) pathway inhibitors and poor clinical outcomes. Through Hi-C analyses of a panel of patient-derived xenograft tumors, here we report drastically different 3D chromatin architectures between NEPC and CRPC samples. Such chromatin re-organization was faithfully recapitulated in vitro on isogenic cells undergoing NE transformation (NET).

TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk.

TDP-43 is an RNA/DNA-binding protein that forms aggregates in various brain disorders. TDP-43 engages in many aspects of RNA metabolism, but its molecular roles in regulating genes and transposable elements (TEs) have not been extensively explored. Chronic TDP-43 knockdown impairs cell proliferation and cellular responses to DNA damage.

Ectopic transcription due to inappropriately inherited histone methylation may interfere with the ongoing function of terminally differentiated cells.

How mutations in histone modifying enzymes lead to neurodevelopmental disorders is unknown. We took advantage of the invariant embryonic lineage and adult nervous system in C. elegans to investigate a double mutant between spr-5/Lsd1/Kdm1a (H3K4me1/2 demethylase) and met-2/Setdb1 (H3K9 methyltransferase).