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Developmental Biology - X Chromosomes

How X Chromosomes 'Talk' to Each Other

How do female humans and all other mammals decide which of two X chromosomes become active or silent?...

Researchers at Massachusetts General Hospital (MGH) have solved a mystery that has long puzzled scientists: How do the bodies of female humans and all other mammals decide which of the two X chromosomes it carries in each cell should be active and which one should be silent?

In a breakthrough study published in Nature Cell Biology, the MGH team discovered the role of a critical enzyme in a phenomenon known as X chromosome inactivation (XCI), which is essential for normal female development and also sets the stage for genetic disorders known as X-linked diseases (such as Rett Syndrome) to occur.
Scientists have known for over a half century that female mammals undergo XCI during embryo formation.

Females have two copies of the X chromosome. Each carry many genes. To have all these genes expressed (functioning) on each X would be toxic to a cell. Just as toxic as if both X chromosomes did not express any functioning genes.

To avoid either fate, females evolved a mechanism to inactivate, or silence, one X chromosomes during embryo formation.

Over the years, investigators have made strides in understanding how XCI occurs. In 2006, a team led by Jeannie Lee MD PhD, Department of Molecular Biology at MGH, reported that during embryo development both X chromosomes briefly come together, or pair. Lee and her colleagues have since uncovered conclusive evidence that pairing is needed by the body to decide which X chromosome to inactive.
"Until now, no one knew what one X chromosome was saying to the other to make this decision."

Jeannie T. Lee MD PhD, Department of Molecular Biology at MGH, Director of Lee Laboratory and professor of Genetics, Harvard Medical School. Senior author.

To find out, Lee and her colleagues had to develop sophisticated molecular tools that allow them to study key proteins involved in XCI, proteins previously difficult to measure.

DCP1A Flips The Switch

It was already known that, prior to pairing, both X chromosomes are identical, or "symmetrical," meaning that each expresses the same genes.

Importantly, both chromosomes also express a form of noncoding RNA called Xist, vital for inactivating an X chromosome. However, both X chromosomes also express another form of RNA — Tsix — which blocks Xist and prevents XCI.
Now the team has found the enzyme DCP1A randomly binds to one of the X chromosomes.

This action "decaps" the chromosome's protective cover of Tsix, making its RNA unstable. As DCP1A only exists in tiny amounts — just enough to bind to only one X chromosome — decapping flips the switch beginning inactivation of one of two X chromosomes.

This allows the protein CTCF - "glue" holding X chromosomes together during pairing — to bind to the unstable Tsix RNA shutting it down permanently.

"DCP1A allows the two X chromosomes to have a fateful 'conversation'. This discovery will help scientists understand how other molecular conversations take place within a cell," explains Lee, laboratory director.

How allelic asymmetry is generated remains a major unsolved problem in epigenetics. Here we model the problem using X-chromosome inactivation by developing “BioRBP”, an enzymatic RNA-proteomic method that enables probing of low-abundance interactions and an allelic RNA-depletion and - tagging system. We identify messenger RNA-decapping enzyme 1A (DCP1A) as a key regulator of Tsix, a noncoding RNA implicated in allelic choice through X-chromosome pairing. DCP1A controls Tsix half-life and transcription elongation. Depleting DCP1A causes accumulation of X–X pairs and perturbs the transition to monoallelic Tsix expression required for Xist upregulation. While ablating DCP1A causes hyperpairing, forcing Tsix degradation resolves pairing and enables Xist upregulation. We link pairing to allelic partitioning of CCCTC-binding factor (CTCF) and show that tethering DCP1A to one Tsix allele is sufficient to drive monoallelic Xist expression. Thus, DCP1A flips a bistable switch for the mutually exclusive determination of active and inactive Xs.

Eric Aeby, Hun-Goo Lee, Yong-Woo Lee, Andrea Kriz, Brian C. del Rosario, Hyun Jung Oh, Myriam Boukhali, Wilhelm Haas and Jeannie T. Lee.

This work was supported by an Advanced Postdoc Mobility Fellowship from the Swiss National Science Foundation (SNSF) to E.A., an NSF Predoctoral Fellowship and Herschel Smith Fellowship to A.K. and grants from the NIH (R01-GM58839) and the Howard Hughes Medical Institute to J.T.L. We thank B. Nabet and N. S. Gray for advice in generating the CTCF–FKBPdegron line and for the generous gift of dTAG-13; C. Cifuentes-Rojas, M. Blower, A. J. Hernandez, Y. Jeon and A.-S. Reis for technical advice and discussion; D. Trono and I. Barde for lentiviral constructs; E. Heard for sharing the XTetOXTetO/laminB cells; W. Press for mouse management; D. Colognori for oligonucleotides FISH probes; and L. Carrette, Y. Jeon, A. Szanto, J. E. Froberg, R. Aguilar and C. Y. Wang for qPCR primers.

Author Notes
These authors contributed equally: Hun-Goo Lee, Yong-Woo Lee.

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
Eric Aeby, Hun-Goo Lee, Yong-Woo Lee, Andrea Kriz, Brian C. del Rosario, Hyun Jung Oh & Jeannie T. Lee.

Department of Genetics, Harvard Medical School, Boston, MA, USA
Eric Aeby, Hun-Goo Lee, Yong-Woo Lee, Andrea Kriz, Brian C. del Rosario, Hyun Jung Oh & Jeannie T. Lee

About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1B and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2020 the MGH was named the #6 hospital in the United States in the U.S. News & World Report list of "America's Best Hospitals." Massachusetts General Hospital Cancer Center, Boston, MA, USA
Myriam Boukhali & Wilhelm Haas

Department of Medicine, Harvard Medical School, Boston, MA, USA
Myriam Boukhali & Wilhelm Haas.

E.A. and J.T.L. designed the project, analysed data and wrote the paper. E.A. established Tsix allele-specific targeting, Xist and Tsix BioRBP, and performed DCP1A, FISH and ChIP experiments. E.A. performed PRO-seq and RNA-seq experiments. Y.-W.L. performed pairing assays in CTCF–FKBPdegron and XTetOXTetO/laminB cells. H.-G.L. conducted DRIP-seq and PRO-seq bioinformatic analyses with assistance from E.A. A.K. constructed the CTCF–FKBPdegron cell lines. B.C.d.R. performed the apoptosis analysis in mouse embryos with assistance from E.A. H.J.O. performed allelic CTCF ChIP experiments with E.A. Mass spectrometry analysis was conducted by M.B. and W.H.

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Aug 26 2020   Fetal Timeline   Maternal Timeline   News

Research from Massachusetts General Hospital has identified that the DCPiA enzyme randomly blocks Tsix (a form of RNA) on one X chromosome making it inactive. This allows an egg to fertilize with a sperm. CREDIT Image in the Public Domain.

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