Weekly reads: H3.3 on the brain, Texas bill, HSCs

It’s always exciting when your lab has a new paper and my team just published a study knocking out the H3f3a gene in mice, which codes for histone H3.3 protein. We found that loss of this gene leads to lethality at a late stage of embryonic development. There were also indications of more specific phenotypes including a small brain and particularly small lungs.

Here’s the new paper in Genesis: A knockout-first model of H3f3a gene targeting leads to developmental lethality.

H3f3a, histone H3.3, knockout
H3f3a histone H3.3 coding gene knockout embryo exhibits several potential phenotypes including small lungs and brains. Fig. 2f, Bush, et al. Genesis, 2023.

H3.3 knockouts

My team also made neurospheres (neural stem and precursor cell) cultures from H3f3a knockout embryos and found some notable gene expression changes. Interestingly, while we in parallel made H3f3a knockout mouse embryonic fibroblasts or MEF cultures too, they didn’t exhibit almost any change in gene expression. This is likely because two genes encode identical H3.3 protein: H3f3a and H3f3b. As a result, our H3f3a knockout MEFs still have H3f3b present and so can make some H3.3 that way. In fact, our previous study pointed to H3f3b producing most of the H3.3 protein in MEFs. In contrast, we think it’s likely that H3f3a produces more of the H3.3 in neural stem cells.

These studies have some important translational implications. In humans H3F3A is mutated both in glioma and also in different ways in neurodevelopmental disorders. In the latter, sometimes H3F3B can be mutated instead. Our lab is studying both the normal roles of H3.3 in development and its disease-related functions in brain tumors and neurodevelopmental disorders. It looks like there will be synergism between these two arms of the H3.3 work. For example, understanding normal H3.3 function in the brain is likely to shed light on what mutant H3.3 does to cause glioma.

Before I go on to more recommended reads, please check out our stem cell YouTube channel and subscribe. We’ve crossed 40,000 views so that’s cool. I’ve included one of our videos below.

Recommended reads

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