Post-transcriptional cross- and auto-regulation buffer expression of the human RNA helicases DDX3X and DDX3Y
- 1Whitehead Institute, Cambridge, Massachusetts 02142, USA;
- 2Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 3Departments of Bioengineering, Biology, Chemistry, and Chemical Biology, Single Cell Proteomics Center, and Barnett Institute, Northeastern University, Boston, Massachusetts 02115, USA;
- 4Howard Hughes Medical Institute, Whitehead Institute, Cambridge, Massachusetts 02142, USA
Abstract
The Y-linked gene DDX3Y and its X-linked homolog DDX3X survived the evolution of the human sex chromosomes from ordinary autosomes. DDX3X encodes a multifunctional RNA helicase, with mutations causing developmental disorders and cancers. We find that, among X-linked genes with surviving Y homologs, DDX3X is extraordinarily dosage sensitive. Studying cells of individuals with sex chromosome aneuploidy, we observe that when the number of Y Chromosomes increases, DDX3X transcript levels fall; conversely, when the number of X Chromosomes increases, DDX3Y transcript levels fall. In 46,XY cells, CRISPRi knockdown of either DDX3X or DDX3Y causes transcript levels of the homologous gene to rise. In 46,XX cells, chemical inhibition of DDX3X protein activity elicits an increase in DDX3X transcript levels. Thus, perturbation of either DDX3X or DDX3Y expression is buffered: by negative cross-regulation of DDX3X and DDX3Y in 46,XY cells and by negative auto-regulation of DDX3X in 46,XX cells. DDX3X–DDX3Y cross-regulation is mediated through mRNA destabilization—as shown by metabolic labeling of newly transcribed RNA—and buffers total levels of DDX3X and DDX3Y protein in human cells. We infer that post-transcriptional auto-regulation of the ancestral (autosomal) DDX3X gene transmuted into auto- and cross-regulation of DDX3X and DDX3Y as these sex-linked genes evolved from ordinary alleles of their autosomal precursor.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.279707.124.
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Freely available online through the Genome Research Open Access option.
- Received July 8, 2024.
- Accepted November 26, 2024.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
