Early in the development of female mammals, one of the two X chromosomes is silenced in half of cells and the other X chromosome is silenced in the remaining half. The basis of this apparent randomness is not understood. We show that before X-inactivation, the two X chromosomes appear to exist in distinct states that correspond to their fates as the active and inactive X chromosomes. Xist and Tsix, noncoding RNAs that control X chromosome fates upon X-inactivation, also determine the states of the X chromosomes prior to X-inactivation. In wild-type ES cells, X chromosomes switch between states; among the progeny of a single cell, a given X chromosome exhibits each state with equal frequency. We propose a model in which the concerted switching of homologous X chromosomes between mutually exclusive future active and future inactive states provides the basis for the apparently random silencing of one X chromosome in female cells.

XIST

Dosage compensation

10.1371/journal.pbio.0040159

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Citations (65)

X-chromosome inactivation: the molecular basis of silencing

Journal of Biology (2008)

Barbara Panning

X-chromosome inactivation occurs randomly for one of the two X chromosomes in female cells during development. Inactivation occurs when RNA transcribed from the Xist gene on the X chromosome from which it is expressed spreads to coat the whole X chromosome. In the first issue of Epigenetics and Chromatin, Nesterova and colleagues investigate the role of the RNA interference pathway enzyme Dicer in DNA methylation of the Xist promoter.

XIST

Dicer

Dosage compensation

10.1186/jbiol95

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Citations (51)

The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Harold C. Marin Eric Simental Charlie Allen Eric S. Martin Barbara Panning

Abstract Heterochromatic loci marked by histone H3 lysine 9 dimethylation (H3K9me2) are enriched at the nuclear periphery in metazoans, but the effect of spatial position on heterochromatin function has not been defined. Here, we remove three nuclear lamins and lamin B receptor (LBR) in mouse embryonic stem cells (mESCs) and show that heterochromatin detaches from the nuclear periphery. Mutant mESCs sustain naïve pluripotency and maintain H3K9me2 across the genome but cannot repress H3K9me2-marked genes or transposons. Further, mutant cells fail to differentiate into epiblast-like cells (EpiLCs), a transition that requires the expansion of H3K9me2 across the genome. Mutant EpiLCs can silence naïve pluripotency genes and activate epiblast-stage genes. However, H3K9me2 cannot repress markers of alternative fates, including primitive endoderm. We conclude that the nuclear periphery controls the spatial position, dynamic remodeling, and repressive capacity of H3K9me2-marked heterochromatin to shape cell fate decisions.

Cell fate determination

Nuclear gene

10.1101/2024.07.08.602542

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The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2006)

Sundeep Kalantry Kyle C. Mills Della Yee Arie P. Otte Barbara Panning

Polycomb-group proteins

10.17615/a8ph-s607

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The zinc finger protein Zn72D and DEAD box helicase Belle interact and control maleless mRNA and protein levels

BMC Molecular Biology (2009)

Kathleen A. Worringer Feixia Chu Barbara Panning

Abstract Background The Male Specific Lethal (MSL) complex is enriched on the single X chromosome in male Drosophila cells and functions to upregulate X-linked gene expression and equalize X-linked gene dosage with XX females. The zinc finger protein Zn72D is required for productive splicing of the maleless ( mle ) transcript, which encodes an essential subunit of the MSL complex. In the absence of Zn72D, MLE levels are decreased, and as a result, the MSL complex no longer localizes to the X chromosome and dosage compensation is disrupted. To understand the molecular basis of Zn72D function, we identified proteins that interact with Zn72D. Results Among several proteins that associate with Zn72D, we found the DEAD box helicase Belle (Bel). Simultaneous knockdown of Zn72D and bel restored MSL complex localization to the X chromosome and dosage compensation. MLE protein was restored to 70% of wild-type levels, although the level of productively spliced mle transcript was still four-fold lower than in wild-type cells. The increase in production of MLE protein relative to the amount of correctly spliced mle mRNA could not be attributed to an alteration in MLE stability. Conclusion These data indicate that Zn72D and Bel work together to control mle splicing and protein levels. Thus Zn72D and Bel may be factors that coordinate splicing and translational regulation.

Dosage compensation

RNA Helicase A

DEAD box

Splicing factor

10.1186/1471-2199-10-33

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Citations (20)