Eukaryotic genomes are pervasively transcribed to produce diverse lncRNAs. Although it still remains undetermined how many of these lncRNAs are functional, it is suspected that they are involved in several crucial cellular processes. With that in mind, I began my research by asking: “how are lncRNAs regulated?” and “which are the functional
lncRNAs in certain cellular process, and how do they exert their functions?”.
To explore the mechanisms of how lncRNAs are regulated, I studied the maturation event of lncRNA MALAT1. MALAT1 is a highly abundant lncRNA, which localizes to nuclear speckles and is implicated in pre-mRNA splicing and transcriptional activation of genes involved in cell-growth and proliferation (Li et al, 2009; Tripathi et al, 2010; Tripathi et al, 2013; Yang et al, 2011b; Zong et al, 2011). The strikingly high cellular accumulation of MALAT1 [MALAT1 exists in ~2500-3000 copies per cell (Tripathi et al, 2010), with a half-life up to 16.5 hours (Gutschner et al, 2013)] has been attributed to an unusual processing and maturation event at its ultra-conserved 3’ end, which involves the
cleavage of mascRNA, a tRNA-like structure, out of the primary transcript, followed by the formation of a bipartite triple helical structure at its 3’ end, which confers resistance against exonucleases-mediated RNA degradation (Brown et al, 2014; Brown et al, 2012;
Wilusz et al, 2008; Wilusz et al, 2012) . In Chapter 2, I identified TALAM1, a NAT from the MALAT1 locus, as an important positive regulator of MALAT1 through promoting its 3’ end processing event, which is crucial for its stability. TALAM1 was found to be essential for the cellular accumulation of MALAT1 and could potentiate the stabilization effect of MALAT1 3’ end sequence towards labile RNA. Further, TALAM1 itself is positively regulated by MALAT1, thereby forming a feed-forward regulatory loop to maintain the high cellular levels of MALAT1.
It remains to be elucidated how TALAM1 modulates the 3’ end cleavage of MALAT1.
TALAM1 RNA concentrates predominantly at the MALAT1 gene locus and could form
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RNA duplex structures with MALAT1 RNA. At the same time, exogenous expression studies indicate that TALAM1 could also exert its function in trans. It is possible that TALAM1, by interacting with MALAT1, modulates the secondary and tertiary structure of MALAT1 RNA, and this could influence the recognition of mascRNA by RNase P. It is also possible that TALAM1 may facilitate the recruitment of specific components of the RNase P complex or its cofactors to MALAT1 RNA, or act as a decoy to sponge inhibitory protein factors away from MALAT1 RNA. Future studies could probe into the mechanistic insights of TALAM1, and potentially other NATs, in RNase P-mediated cleavage of non-canonical substrates, including MALAT1 and additional cellular RNAs with ENE-like structures.
In addition, given the fact that the aberrant upregulation of MALAT1 is observed to be widely associated with hyper-proliferation and metastasis in cancer, and the oncogenic activity of MALAT1 has been documented in several types of cancers (Gutschner et al, 2013), it would be interesting to determine whether specific oncogenic pathways regulate TALAM1 levels in order to increase MALAT1 levels. In this context, it would be fruitful to profile human cancers with upregulated MALAT1 levels, and determine whether the elevated MALAT1 levels are attributed to its enhanced stability, altered efficiency in 3’
end processing and dysregulated expression of TALAM1. These analyses will help us to understand the aberrant upregulation of MALAT1 and may provide clinical clues to modulate its level in cancers.
To study the roles and mechanisms of action of novel lncRNAs in vital cellular processes, I chose to study the functional lncRNAs in cell cycle progression. Proper regulation of cell division cycle is crucial to the growth and development of all organisms.
Understanding this regulation is central to the study of many diseases, most notably cancer. In Chapter 3, through a genome-wide unbiased lncRNA transcriptome analysis in cell cycle-synchronized cells, we identified ~400 lncRNAs that exhibit cell cycle-specific
99
expression patterns. Functional characterization of one S phase-upregulated lncRNA, S7, revealed its important roles in regulating cell cycle progression and DNA damage
response. S7 regulates a group of genes involved in cell proliferation and DDR in cis, among which is WTIP, a member of AJUBA family proteins that represses Hippo signaling pathway. The Hippo pathway controls organ size and tissue homeostasis in diverse species through regulating cell proliferation, apoptosis and stemness, whereas the deregulation of this pathway underlie a broad range of human carcinomas(Yu et al, 2015).
I therefore have identified S7 as an important lncRNA inhibitor of Hippo pathway and thereby playing critical roles in regulating cell cycle progression and tumorigenesis. It would be imperative to profile the cancer types where S7 locus is amplified to determine whether these cancer types are addicted to the repression of Hippo pathway, and whether manipulation of S7’s level could provide clinical benefits to these cancers.
With respect to the molecular mechanism of action, our results imply that the regulation of WTIP transcription by S7 may occur through S7’s recruitment of DDX5 to WTIP promoter. DDX5 is a member of the DEAD box family with RNA helicase activity. In addition to its crucial roles in RNA metabolism, it is becoming increasingly clear that DDX5 acts as transcription cofactor(Fuller-Pace, 2013). Future studies will address whether S7 affects the binding of DDX5 to WTIP promoter, and whether S7 is directly involved in the recruitment of DDX5 to WTIP promoter. For the potential direct role of S7 in recruiting DDX5 to WTIP promoter, it is possible that S7 RNA is present in a complex with DDX5 at WTIP promoter, and the presence of S7 lncRNA may either confer specificity in targeting DDX5 to WTIP promoter, and/or stimulate the
transcriptional co-activator activity of DDX5. Two lncRNAs have recently been reported to modulate the activity and chromatin recruitment of DEAD box family proteins,
including DDX5(Huang et al, 2015; Marchese et al, 2016). We therefore speculate that the mode of action of S7 may represent a more widely spread mechanism in which
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lncRNAs interacts with the DEAD box family DNA/RNA helicases to modulate their location and activity.
Furthermore, as exemplified by S7, it would be fruitful to characterize the other cell cycle-regulated lncRNAs identified in our study in the future, which may reveal
additional lncRNAs that are important for cell cycle regulation and cancer development.
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