SAF-A Regulates Interphase Chromosome Structure through Oligomerization with Chromatin-Associated RNAs

Abstract

SummaryHigher eukaryotic chromosomes are organized into topologically constrained functional domains; however, the molecular mechanisms required to sustain these complex interphase chromatin structures are unknown. A stable matrix underpinning nuclear organization was hypothesized, but the idea was abandoned as more dynamic models of chromatin behavior became prevalent. Here, we report that scaffold attachment factor A (SAF-A), originally identified as a structural nuclear protein, interacts with chromatin-associated RNAs (caRNAs) via its RGG domain to regulate human interphase chromatin structures in a transcription-dependent manner. Mechanistically, this is dependent on SAF-A’s AAA+ ATPase domain, which mediates cycles of protein oligomerization with caRNAs, in response to ATP binding and hydrolysis. SAF-A oligomerization decompacts large-scale chromatin structure while SAF-A loss or monomerization promotes aberrant chromosome folding and accumulation of genome damage. Our results show that SAF-A and caRNAs form a dynamic, transcriptionally responsive chromatin mesh that organizes large-scale chromosome structures and protects the genome from instability.

Differential contribution of steady‐state RNA and active transcription in chromatin organization

“…Indeed, although the compartmentalization was not markedly altered (Fig ) we observed a reduction in TAD boundary strength upon transcriptional inhibition (Fig ). These results are concordant with a model where the act of transcription and or its product influences the nuclear positioning of the newly transcribed DNA locus via interaction with nuclear matrix proteins .…”

“…More recently, active transcription has also been postulated as a major driving force in shaping genome architecture [26][27][28][29]. Not only was it shown that transcriptional elongation can remodel 3D genome structure [30,31], but transcription can also affect TAD interactions [26,32].…”

FANCD2 protects genome stability by recruiting RNA processing enzymes to resolve R‐loops during mild replication stress

“…In this study, we showed that R‐loop levels were increased in FANCD2 ‐depleted cells following APH treatment. We also provided evidence for an interaction of FANCD2 with hnRNP U, an RNA‐binding protein that functions in transcription elongation , pre‐mRNA splicing , mRNA stability , and more broadly, interphase chromatin structures . Given the function of hnRNP U in normal RNA metabolism, it is not surprising that hnRNP U function contributes to the regulation of R‐loop levels.…”

Transcription organizes euchromatin similar to an active microemulsion

“…For example, the non-coding RNAs Xist and Firre establish chromatin microarchitectures (Engreitz et al, 2013;Hacisuleyman et al, 2014). Furthermore, chromatin associated RNAs are required for efficient oligomerization of SAF-A protein, which results in decompaction of transcribed euchromatin (Nozawa et al, 2017). The above suggests that transcription as well as RNA have roles in the organization of euchromatin.…”