Neurogenesis occurs in the olfactory system of the adult brain throughout life, in both invertebrates and vertebrates, but its physiological regulation is not understood. We show that the production of neuronal progenitors is stimulated in the forebrain subventricular zone of female mice during pregnancy and that this effect is mediated by the hormone prolactin. The progenitors then migrate to produce new olfactory interneurons, a process likely to be important for maternal behavior, because olfactory discrimination is critical for recognition and rearing of offspring. Neurogenesis occurs even in females that mate with sterile males. These findings imply that forebrain olfactory neurogenesis may contribute to adaptive behaviors in mating and pregnancy.

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Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumors, such as glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention. We show, using single-cell chromatin accessibility, that primary human GBMs harbor a heterogeneous self-renewing population whose diversity is captured in patient-derived glioblastoma stem cells (GSCs). In-depth characterization of chromatin accessibility in GSCs identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely essential transcription factors and present within GBMs in varying proportions. Orthotopic xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature predictive of low patient survival, in line with the higher invasive properties of Invasive state GSCs compared to Reactive and Constructive GSCs as shown by in vitro and in vivo assays. Our chromatin-driven characterization of GSC states improves prognostic precision and identifies dependencies to guide combination therapies.

41Chromatin accessibility discriminates stem from mature cell populations, enabling the 42 identification of primitive stem-like cells in primary tumors, such as Glioblastoma (GBM) where 43 self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic 44 intervention. We show, using single-cell chromatin accessibility, that primary GBMs harbor a 45 heterogeneous self-renewing population whose diversity is captured in patient-derived 46 glioblastoma stem cells (GSCs). In depth characterization of chromatin accessibility in GSCs 47 identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely 48 essential transcription factors and present within GBMs in varying proportions. Orthotopic 49 xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature 50 predictive of low patient survival. Our chromatin-driven characterization of GSC states improves 51 prognostic precision and identifies dependencies to guide combination therapies. 52 53 56only an additional 2.5 months in the small subset of responsive patients [2]. Despite extensive 57 characterization and stratification of the bulk primary tumors, no targeted therapies have been 58 successfully developed [1,3]. GBM tumors are rooted in self-renewing tumor-initiating cells 59 commonly referred to as glioblastoma stem cells (GSCs)[4] that drive disease progression in 60 vivo [5,6] and display resistance to chemo-and radiotherapy leading to disease recurrence [7]. 61 The promise of therapeutically targeting self-renewing tumor-initiating cancer cells depends on 62 3 our capacity to capture the full range of heterogeneity within this population from individual 63 tumors. Intratumoral heterogeneity within primary GBM has recently been documented 64 through single cell RNA-seq experiments and revealed a continuum between four cellular 65 states[8]: neural-progenitor-like (NPC), oligodendrocyte-progenitor-like (OPC), astrocyte-like 66 (AC), and mesenchymal-like (MES)[8]. A subsequent study[9] using single-cell gene-centric 67 enrichment analysis placed GBM cells along a single axis of variation from proneural to 68 mesenchymal transcriptional profiles, with cells expressing stem-associated genes lying at the 69 extremes of this axis. Hence, primary GBM consists of distinct states, across which stem-like 70 cells appear to be found. Whether these stem-like cells found across GBM states represent 71 functionally distinct GSC populations with tumor-initiating properties and unique dependencies 72 remains to be established to guide therapeutic progress. To address this issue, we combined 73 single-cell technologies to define GSC composition in primary GBM with functional assays to 74 reveal the unique dependencies across GSCs, reflective of invasive, constructive and reactive 75 states that relate to patient outcome. 76 77 RESULTS 78Chromatin accessibility readily discriminates stem from mature cell populations [10], 79 which can be resolved at the single cell level thro...

Brain tumour stem cell population in glioblastoma (GBM) display key cancer stem cell characteristics of high self-renewal and drug resistance that are maintained by the coordinated functions of epigenetic and molecular regulators. Yet, specific epigenetic mechanisms that, in collaboration with relevant molecular pathways, help maintain a stem-like state in BTSCs remain poorly understood. Here, we identify HDAC2 as a foremost epigenetic regulator in BTSCs that specifically utilizes the transforming growth factor-β (TGF-β) pathway related proteins, SMAD3-SKI, for remodelling BTSC chromatin accessibility and transcriptional programs to facilitate their stemness and tumorigenic potentials. Our initial drug screening revealed that selective inhibition of HDAC1 and 2 with romidepsin was effective in targeting BTSC viability, cell proliferation and self-renewal in vitro. Using CRISPR-cas9 knockout and shRNA knockdown strategies, we further demonstrated that loss of HDAC2 disrupts an epigenetic and molecular coordination between HDAC2 and SMAD-SKI proteins, which negatively impacts BTSC survival, cell proliferation and self-renewal in vitro and improves median survival in orthotopic xenograft mouse models. Loss of HDAC2 showed reduction in the protein abundance of transcriptional regulator, SMAD3 and negative regulator protein, SKI. However, overexpression of SMAD3 in HDAC2 deficient BTSCs could partially rescues their cell functional deficits. These findings suggest that context-specific epigenetic regulations by HDAC2 and its interaction with the critical transcriptional regulators, SMAD3-SKI, maintains the stemness and growth characteristics of BTSCs. Further HDAC2 overexpression increases cell proliferation and self-renewal abilities in normal neural stem cells (NSCs). These findings thus support the role of HDAC2 as a key epigenetic determinant of stemness in normal NSCs and of cancer stem cell characteristics and tumorigenic potential in BTSCs. Collectively, our data raises the potential that disruption of the coordinated mechanisms regulated by HDAC2-SMAD3-SKI axis may be an effective therapeutic approach for targeting GBM BTSCs.