Long non-coding RNAs: roles in cellular stress responses and epigenetic mechanisms regulating chromatin

Figures & data

Figure 1. Cytoplasmic and nuclear mechanisms for lncRNAs. This summarizes just a few of the molecular mechanisms by which lncRNAs can function. This figure was created with BioRender.com.

Diagram of a subset of lncRNA molecular mechanisms operating in the nucleus or in the cytoplasm.

Table 1. Function of selected additional lncRNAs in cellular stress.

Long non-coding RNA	Function	Ref
HOTAIR (HOX Transcript Antisense RNA)	Modulates the cellular stress response by affecting the p53 pathway and influencing histone modification patterns.	[5]
MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1)	Regulates the expression of genes associated with cell cycle and survival pathways, thereby affecting the cellular response to hypoxia and oncogenicstress.	[6]
NEAT1 (Nuclear Enriched Abundant Transcript 1)	Plays a role in the cellular stress response by sequestering certain RNAs and RNA-binding proteins, thereby influencing their activity and availability inthe cell; involved in the cellular response to viral infections and hypoxic stress.	[7]
GAS5 (Growth Arrest-Specific 5)	Accumulates in growth-arrested cells and regulates the stress response by acting as a glucocorticoid receptor riborepressor and influencing apoptosis and cell cycleregulation.	[8]
H19	Modulates the cellular stress response, particularly in hypoxia and nutrient deprivation, by regulating autophagy and apoptosis pathways.	[9]
LincRNA-p21	Involved in p53-mediated cellular stress responses, affecting apoptosis and cell cycle arrest following DNA damage.	[10]
ANRIL (Antisense Non-coding RNA in the INK4 Locus)	Regulates gene expression associated with cell cycle control and is implicated in cellular senescence and the response to DNA damage.	[11]
MEG3 (Maternally Expressed Gene 3)	Acts as a tumor suppressor and is involved in p53-mediated stress responses, influencing cell proliferation and apoptosis.	[12]
NORAD (Noncoding RNA Activated by DNA Damage)	Maintains genomic stability by sequestering proteins that are involved in theDNA damage response, thus playing a role in the cellular response to DNA damage stress.	[13]
CYTOR (Cytoskeleton Regulator RNA)	Involved in the regulation of the cytoskeleton, cellular morphology, and stress fiber formation, which is important for cells responding to mechanical stress.	[14]
PANDA (P21 Associated ncRNA DNA Damage Activated)	Over Expression Promotes Hepatocellular Carcinoma by Inhibiting Senescence Associated Inflammatory Factor IL8	[15]
FENDRR (FOXF1 Adjacent Non-Coding Developmental Regulatory RNA)	Plays a critical role in heart and body wall development in the embryo and is involved in the regulation of several transcription factors and epigenetic regulators under stress conditions.	[16,17]
HIF1A-AS2 (HIF1A Antisense RNA 2	Associated with the regulation of HIF-1α, a key transcription factor that mediates cellular response to hypoxia. By influencing the stability and activity of HIF-1α, HIF1A-AS2 plays a significant role in the cellular adaptation to low oxygen levels.	[18,19]
UCA1 (Urothelial Cancer Associated 1)	Promotes cell survival under low oxygen conditions by regulating the expression of HIF-1α and its downstream targets, thus playing a role in tumor progression and resistance to therapy.	[20]
GAS5 (Growth Arrest-Specific 5)	Acts as a tumor suppressor in various cancers and influences autophagy by modulating the mTOR signaling pathway. It can enhance autophagy undernutrient starvation conditions, contributing to its role in tumor suppression andresponse to stress.	[21]
TERRA (Telomeric Repeat-Containing RNA)	Transcribed from telomeres and contributes to the maintenance of telomere integrity. It is involved in the response to telomeric DNA damageand interacts with the telomeric shelterin complex, influencing genomic stability.	[22]
LINC-PINT (Long Intergenic Non-Protein Coding RNA, P53 Induced Transcript)	Induced by p53 and plays a role in regulating cell proliferation and apoptosis in response to DNA damage. It interacts with polycomb repressive complexes and other chromatin modifiers to regulate the expression of p53-target genes involved in the DNA damage response.	[23]

Figure 2. The RNP network of the nucleus is well preserved after chromatin removal. Shown are epon sections of CaSki cervical carcinoma cells before (a) and after (b) the isolation of a crosslink stabilized nuclear matrix and selectively stained for RNA by the EDTA- regressive procedure [76] to visualize the RNP-network. The nuclear lamina (L) forms the periphery of the nucleus (panel A) and is retained in the nuclear matrix (panel B). The removal of chromatin after formaldehyde crosslinking does not substantially alter the structure or spatial distribution of the nuclear RNP network. (c) Higher magnification reveals well-preserved interchromatin granule clusters, enriched in RNA-splicing factors, in the RNP-network of the crosslink-stabilized nuclear matrix. The CaSki nuclear matrix in this panel was counterstained with an antibody recognizing the RNA-splicing factor SRm160 and a colloidal-gold-conjugated second antibody. The bar in panels a and B is 500 nm and in panel C the bar is 200 nm. This is from Figure 4 of Nickerson et al. [82].

Electron micrographic comparison showing that the distribution of RNA, as detected by EDTA regressive staining is conserved after the removal of chromatin.

Figure 3. The RNP network of a CaSki cell isolated after crosslink-stabilization and chromatin removal. When visualized by resinless section electron microscopy. (a) The RNP network or nuclear matrix consists of two parts, the nuclear lamina (L) and a network of structured fibers connected to the lamina and well distributed through the nuclear volume. The matrices of nucleoli (nu) remain and are connected to the fibers of the internal nuclear matrix. Three remnant nucleoli may be seen in this section. (b) Seen at higher magnification, the highly structured fibers of an internal RNP-netork or nuclear matrix are constructed on an underlying structure of 10-nm filaments, which occasionally branch. These are seen most clearly when, for short stretches, they are free of covering material (arrowheads). The bar shown in panel a represents 1 µM, and in panel B it is 100 nm. This is from Figure 3 of Nickerson et al., 1997 [82].

Electron micrographs of the nucleus after crosslinking and then the removal of chromatin showing a peripheral nuclear lamina connected to an internal network of fibers.

Figure 4. The RNA-containing nuclear matrix from a HeLa cell when isolated without a cross-linking step before the removal of chromatin. The structure is constructed on a branched network of 10-nm core filaments that resemble filaments that form in phase-separated condensates of RNP proteins [169,177–179]. This high magnification view shows connections between core filaments (arrow) and the nuclear lamina (L). The bar is 100nM [180].

Electron micrographs showing a nucleus with chromatin removed without a prior crosslinking step, revealing a network of branched 10nm filaments.

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.