RNF12 is an X-Encoded dose-dependent activator of X chromosome inactivation.
In somatic cells of female placental mammals, one X chromosome is inactivated to minimize sex-related dosage differences of X-encoded genes. Random X chromosome inactivation (XCI) in the embryo is a stochastic process, in which each X has an independent probability to initiate XCI, triggered by the nuclear concentration of one or more X-encoded XCI-activators. Here, we identify the E3 ubiquitin ligase RNF12 as an important XCI-activator. Additional copies of mouse Rnf12 or human RNF12 result in initiation of XCI in male mouse ES cells and on both X chromosomes in a substantial percentage of female mouse ES cells. This activity is dependent on an intact open reading frame of Rnf12 and correlates with the transgenic expression level of RNF12. Initiation of XCI is markedly reduced in differentiating female heterozygous Rnf12(+/-) ES cells. These findings provide evidence for a dose-dependent role of RNF12 in the XCI counting and initiation process.
Jonkers
Iris
I
Department of Reproduction and Development, Erasmus MC, University Medical Center, 3000 CA Rotterdam, The Netherlands.
Barakat
Tahsin Stefan
TS
Achame
Eskeatnaf Mulugeta
EM
Monkhorst
Kim
K
Kenter
Annegien
A
Rentmeester
Eveline
E
Grosveld
Frank
F
Grootegoed
J Anton
JA
Gribnau
Joost
J
D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D051379:Mice; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D049951:X Chromosome Inactivation
D012097:Repressor Proteins; C492370:RLIM protein, human; C120758:Rlim protein, mouse; D044767:Ubiquitin-Protein Ligases