Nuclear m⁶A modification regulates satellite transcription and chromosome segregation

The precise location and functions of N⁶-methyladenosine (m⁶A) modification on mammalian nuclear noncoding RNA remain largely unknown. Here we developed nuclear-m⁶A-label-seq to directly map human and mouse cell nuclear RNA m⁶A methylome at single-base resolution. Specifically, m⁶A modifications have been identified on abundant human γ satellite DNA II (GSATII) RNA transcripts, a type of repeat RNA, transcribed from SST1-TAR1-GSATII satellite arrays in the pericentromeric region of chromosome 9. GSATII RNA m⁶A positively regulates the transcription of GSATII-located satellite arrays as well as trans-associated peri/centromeric satellites, typically chromosome 3 centromeric higher-order repeat α satellite. Dysregulation of this circuit renders a phenotype of abnormal chromosome segregation. Mechanistic study reveals that YTHDC1 reads GSATII RNA m⁶A marks and recruits bromodomain protein 4 (BRD4) to promote transcriptions of the associated satellites via an m⁶A-YTHDC1-BRD4-H3K27ac axis. These results uncover a mechanism governing the transcription of cis- and trans-associated pericentromeric and centromeric satellites via cross-talk between epitranscriptomic and epigenomic marks.