Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identify extensive cell-type specific expression changes: 6,711 genes and 10,724 transcripts, enriched in non-protein coding elements at early stages of differentiation. In addition, we discovered 7,881 novel splice junctions and 2,301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrate experimentally cell specific isoform usage, identifying NFIB as a regulator of megakaryocyte maturation -the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.
As a heterogeneous reproductive disorder, polycystic
ovary syndrome
(PCOS) can be caused by genetic, diet, and environmental factors.
Bisphenol A (BPA) can induce PCOS and nonalcoholic fatty liver disease
(NAFLD) due to direct exposure; however, whether these phenotypes
persist in future unexposed generations is not currently understood.
In a previous study, we observed that transgenerational NAFLD persisted
in female medaka for five generations (F4) after exposure to an environmentally
relevant concentration (10 μg/L) of BPA. Here, we demonstrate
PCOS in the same F4 generation female medaka that developed NAFLD.
The ovaries contained immature follicles, restricted follicular progression,
and degenerated follicles, which are characteristics of PCOS. Untargeted
metabolomic analysis revealed 17 biomarkers in the ovary of BPA lineage
fish, whereas transcriptomic analysis revealed 292 genes abnormally
expressed, which were similar to human patients with PCOS. Metabolomic–transcriptomic
joint pathway analysis revealed activation of the cancerous pathway,
arginine–proline metabolism, insulin signaling, AMPK, and HOTAIR
regulatory pathways, as well as upstream regulators esr1 and tgf signaling in the ovary. The present results
suggest that ancestral BPA exposure can lead to PCOS phenotypes in
the subsequent unexposed generations and warrant further investigations
into potential health risks in future generations caused by initial
exposure to EDCs.
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