Abstract
BackgroundMany long noncoding RNAs (lncRNAs) have been implicated in general and cell type-specific molecular regulation. Here, we asked what underlies the fundamental basis for the seemingly random appearance of nuclear lncRNA condensates in cells, and we sought compounds that can promote the disintegration of lncRNA condensates in vivo.ResultsAs a basis for comparing lncRNAs and cellular properties among different cell types, we screened lncRNAs in human pluripotent stem cells (hPSCs) that were differentiated to an atlas of cell lineages. We found that paraspeckles, which form by aggregation of the lncRNA NEAT1, are scaled by the size of the nucleus, and that small DNA-binding molecules promote the disintegration of paraspeckles and other lncRNA condensates. Furthermore, we found that paraspeckles regulate the differentiation of hPSCs.ConclusionsPositive correlation between the size of the nucleus and the number of paraspeckles exist in numerous types of human cells. The tethering and structure of paraspeckles, as well as other lncRNAs, to the genome can be disrupted by small molecules that intercalate in DNA. The structure-function relationship of lncRNAs that regulates stem cell differentiation is likely to be determined by the dynamics of nucleus size and binding site accessibility.Graphical abstract
Highlights
Many long noncoding RNAs have been implicated in general and cell type-specific molecular regulation
The use of human pluripotent stem cells (hPSCs) for studying the functions of long noncoding RNAs (lncRNAs) condensates is advantageous in several respects: first, the differentiation of hPSCs is accompanied by changes of genome architecture [17] that create opportunities to study the formation of lncRNA condensates in cell fate transitions, as we have shown recently for paraspeckles [18]
Dynamics of nuclear lncRNAs in the differentiation of human PSCs To conduct an unbiased assessment of the association of cell types and developmental stages with the expression and condensation of nuclear lncRNAs, we differentiated human PSCs to numerous lineages (Fig. 1a)
Summary
Many long noncoding RNAs (lncRNAs) have been implicated in general and cell type-specific molecular regulation. Nuclear lncRNAs have been implicated in the regulation of gene expression in diverse ways, including the recruitment of chromatin-remodeling complexes of the SWI/SNF family [2], and interaction with Polycomb repressive complexes which modify histones [3]. A notable example are paraspeckles which comprise the lncRNA NEAT1 and RNA-binding proteins (RBPs) that influence gene expression by post-transcriptional regulation of splicing and polyadenylation [5, 6], as well as by interaction with the SWI/SNF complex that remodels nucleosomes [7]. The lncRNA MALAT1, which forms condensates, has been shown to regulate gene expression by interactions with splicing factors [8]. Despite advancements in understanding the composition and formation of lncRNAprotein condensates [9, 10] and separately the functions of RBPs, for example, TDP-43 in the regulation of alternative polyadenylation [11], the regulation mediated together by the Grosch et al BMC Biology (2020) 18:42 aggregation of lncRNAs, RBPs, and other factors is still not well understood
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