Wnt/beta-catenin activity controls the stability of imprinted genes in mouse embryonic stem cells

Theka, Ilda

Wnt/beta-catenin activity controls the stability of imprinted genes in mouse embryonic stem cells

Document Type

Doctoral thesis
Published Version

Author

Theka, Ilda

Director

Cosma, Maria Pia

Publication Date

2017-02-06

Pages

192 p.

Citation

Theka, I. Wnt/beta-catenin activity controls the stability of imprinted genes in mouse embryonic stem cells. Universitat Pompeu Fabra; 2017. handle: http://hdl.handle.net/10803/565761

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

Las células madre embrionarias (ESCs) derivan de la masa cellular interna de los blastocistos y son capaces de generar las tres capas germinales. Muchos factores controlan la pluripotencia incluyendo la ruta Wnt/β-catenina. La implicación de esta ruta en la renovación celular no ha sido aún esclarecida, mientras que su función es indispensable para la diferenciación de ESCs. En esta tesis investigamos como Wnt puede afectar la stabilidad epigenética de las ESCs. Interesantemente, observamos que la reducción de señal Wnt/β-catenina provoca desmetilación del ADN y perdida de represores de la cromatina en varias regiones de control de la impronta genética (ICR). Al contrario, el mantenimiento de Wnt/β-catenina no afectó el estado de los ICR. Además, mostramos que β-catenina puede interaccionar directamente con KAP1 y ZFP57, Finalmente, demostramos que una baja dosis de Wnt/β-catenina es necesaria durante los eventos tempranos de reprogramación cellular, pero la inhibición continua de Wnt perjudica este proceso.
Mouse embryonic stem cells (ESCs) derive from the inner cell mass of the blastocyst and they are able to generate the three germ layers. Many factors control ESC pluripotency including Wnt/β-catenin signaling pathway. The implication of Wnt/β-catenin pathway in self-renewal remains still unclear, whereas its function is indispensable for ESC differentiation. In this study we investigate the effect of Wnt activity on ESC epigenetic stability. Indeed we observed that loss of Wnt/β-catenin signaling causes loss of DNA methylation and chromatin repressors recruitment, such as H3K9me3 and ZFP57, at several imprinted control region (ICR). On the contrary, sustained Wnt/β-catenin signaling protected the ICR status. Moreover, we showed that β-catenin could directly interact with KAP1 and ZFP57 proteins. Finally, we demonstrated that a low dosage of Wnt/β-catenin signaling is necessary during the early stages of somatic cell reprogramming process. However continuous inhibition of Wnt/β-catenin pathway is detrimental to this process.

Keywords

Wnt/β-catenin signaling, Embryonic stem cell, Genomic imprinting, Pluripotent, Cell reprogramming, Ruta de Wnt/β-catenina, Células madre embrionarias, Impronta genética, Pluripotente, Reprogramación celular