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Science Papers Examine Human Fetal Microglia Development, Structure of Adenine Base Editor ABE8e

By analyzing transcriptomic and epigenetic data, researchers from the University of Groningen have characterized human fetal microglia development, providing new insights into the role these central nervous system (CNS) immune cells play in tissue development and disease. As reported in this week's Science, the investigators generated single-cell gene expression and bulk chromatin profiles of microglia at nine to 18 gestational weeks of human fetal development — the point at which these cells start to mature — and find that chromatin accessibility increases during development with associated transcriptional networks reflective of adult microglia. This indicates that it is during early fetal development that microglia gain their mature, CNS-surveilling properties, which explains the vulnerability of the developing human CNS to environmental perturbations at this developmental period during pregnancy.

A high-resolution cryo-electron microscopy structure of the newly discovered CRISPR-Cas9 adenine base editor ABE8e is published in Science this week. ABE8e catalyzes DNA deamination more than 1,000 times faster than other commonly used ABEs, but how it did so was unknown. To better understand this, a team led by University of California, Berkeley, scientists generated the 3.2-angstrom resolution structure of ABE8e in a substrate-bound state in which the deaminase domain engages DNA exposed within the CRISPR-Cas9 R-loop complex. They find that ABE8e's accelerated DNA deamination is due to mutations that stabilize DNA substrates in a constrained, transfer RNA-like conformation. Its high catalytic rate also points to "a previously unobserved transient DNA melting that may occur during double-stranded DNA surveillance by CRISPR-Cas9," they write.