Journal Article

The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting

Donohoe, Mary E., Silva, Susana S., Lee, Jeannie T., Xu, Na, Pinter, Stefan F.

2009

Overview

Pluripotency and the X chromosome During both stem cell differentiation and X chromosome inactivation, the process that silences one female X chromosome to ensure gene dosage parity between the sexes, chromatin undergoes epigenetic reprogramming to lock in a new state. Reprogramming of differentiated cells into iPS cells also causes reactivation of the inactivated X chromosome, and it has been proposed that the pluripotency factor Oct4 links both processes. In this study, Donohoe et al . find that Oct4 regulates X-chromosome inactivation by triggering X-chromosome pairing and counting. Oct4 interacts with both noncoding RNA genes ( Tsix and Xite ) and proteins (Ctcf and Yy1). This work shows that there is a complex network involved in epigenetic reprogramming of the X chromosome in stem cells. During both stem cell differentiation and X-chromosome inactivation (XCI) of mouse embryonic stem cells, chromatin undergoes epigenetic reprogramming. XCI and cell differentiation are tightly coupled, with the blocking of one process compromising the other. The pluripotency factor, Oct4, is now shown to regulate XCI, and is the first identified factor that links both processes. Pluripotency of embryonic stem (ES) cells is controlled by defined transcription factors 1 , 2 . During differentiation, mouse ES cells undergo global epigenetic reprogramming, as exemplified by X-chromosome inactivation (XCI) in which one female X chromosome is silenced to achieve gene dosage parity between the sexes 3 , 4 , 5 . Somatic XCI is regulated by homologous X-chromosome pairing 6 , 7 and counting 8 , 9 , 10 , and by the random choice of future active and inactive X chromosomes. XCI and cell differentiation are tightly coupled 11 , as blocking one process compromises the other 8 , 12 and dedifferentiation of somatic cells to induced pluripotent stem cells is accompanied by X chromosome reactivation 2 . Recent evidence suggests coupling of Xist expression to pluripotency factors occurs 13 , but how the two are interconnected remains unknown. Here we show that Oct4 (also known as Pou5f1) 14 lies at the top of the XCI hierarchy, and regulates XCI by triggering X-chromosome pairing and counting. Oct4 directly binds Tsix and Xite , two regulatory noncoding RNA genes of the X-inactivation centre 15 , 16 , and also complexes with XCI trans-factors, Ctcf and Yy1 (ref. 17 ), through protein–protein interactions. Depletion of Oct4 blocks homologous X-chromosome pairing and results in the inactivation of both X chromosomes in female cells. Thus, we have identified the first trans-factor that regulates counting, and ascribed new functions to Oct4 during X-chromosome reprogramming.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Amino acids / Animals / Binding sites / Biological and medical sciences / CCCTC-Binding Factor / Cell differentiation / Cell differentiation, maturation, development, hematopoiesis / Cell Line / Cell physiology / Chromosome Pairing / Chromosomes / DNA binding proteins / Embryonic stem cells / Female / Fundamental and applied biological sciences. Psychology / Genetic aspects / Humanities and Social Sciences / Humans / Inactivation / letter / Male / Mice / Molecular and cellular biology / multidisciplinary / Octamer Transcription Factor-3 - deficiency / Octamer Transcription Factor-3 - genetics / Octamer Transcription Factor-3 - metabolism / Physiological aspects / Protein Binding / Proteins / Repressor Proteins - metabolism / RNA, Long Noncoding / RNA, Untranslated - genetics / Science / Science (multidisciplinary) / SOXB1 Transcription Factors / Stem cells / Studies / Transcriptional Activation / X chromosome / X Chromosome - genetics / X Chromosome - metabolism / X Chromosome Inactivation - genetics / YY1 Transcription Factor - metabolism