No longer a nuisance: long non-coding RNAs join CENP-A in epigenetic centromere regulation

Abstract

Centromeres represent the basis for kinetochore formation, and are essential for proper chromosome segregation during mitosis. Despite these essential roles, centromeres are not defined by specific DNA sequences, but by epigenetic means. The histone variant CENP-A controls centromere identity epigenetically and is essential for recruiting kinetochore components that attach the chromosomes to the mitotic spindle during mitosis. Recently, a new player in centromere regulation has emerged: long non-coding RNAs transcribed from repetitive regions of centromeric DNA function in regulating centromeres epigenetically. This review summarizes recent findings on the essential roles that transcription, pericentromeric transcripts, and centromere-derived RNAs play in centromere biology.

Keywords: Centromere; Epigenetics; Kinetochore; Long non-coding RNA; Mitosis; Transcription.

Fig. 1

Histone tail modification associated with centromeres. Pericentromeric and centromeric chromatin are distinct from each other. Centromeric chromatin is characterized by the presence of the histone H3 variant CENP-A that replaces H3 in some of the centromeric nucleosomes. Histone modification pattern on canonical histones also vary between centromeric and pericentromeric chromatin

Fig. 2

Transcription from centromeric chromatin influences CENP-A loading in mitosis. The recruitment and activation of RNAPII at centromeres during mitosis may be required to recruit chromatin remodeling complexes such as FACT. FACT can then associate with the loading machinery of CENP-A and facilitates CENP-A loading that may coincide with the transcription of centromeric repeats. Alternatively, the transcription is required to recruit FACT and subsequently the loading machinery of CENP-A to centromeric regions

Fig. 3

Different potential functions of centromeric transcripts. Centromeric RNAs may bind to (or originate from) boundary elements to ensure that different chromatin states can coexists adjacent to each other by maintaining different chromatin identities. Different functional chromatin domains may be maintained this way. Centromeric RNAs have also been suggested to bind centromere-associated proteins and guide them to or stabilize them at centromeres. The guidance may occur in cis on the chromosome of origin of the RNA or in trans on centromeres that do not encode for the centromeric RNA. Last but not least, centromeric transcripts may be part of a higher order chromatin structure that utilizes RNA as a scaffold to maintain a 3D structure crucial for centromere biology. Depicted is a previously suggested hypothetical structure of mitotic centromeres that folds CENP-C-containing domains into an outer platform for kinetochore components [4]. This structure may be established, stabilized or maintained by non-coding RNA from centromeric repeats