Talia Hammer & Sara Lohbauer

The Master of Genomic Programs: HOTAIR in Cellular Development and

Cancer Metastasis

Aquila – The FGCU Student Research Journal Volume 3 Issue 1 (2016)

DOI 10.24049/aq.3.1.6

© 2016 Hammer et al

Distributed under Creative Commons CC-BY 4.0

OPEN ACCESS Aquila - The FGCU Student Research Journal The Master of Genomic Programs: HOTAIR in Cellular Development and Cancer Metastasis

Talia Hammer & Sara Lohbauer

Florida Gulf Coast University, College of Arts & Sciences, Fort Myers, FL 33965

Faculty mentor: Lindsay Rhodes, Ph.D., Florida Gulf Coast University, College of Arts & Sciences, Department of Biological Sciences, Fort Myers, FL 33965

ABSTRACT Originally thought of as “junk RNA”, long non-coding RNA (lncRNA) has been shown over the last decade to play active regulatory roles in many vital cellular processes. The accepted primary mechanism of lncRNA regulatory activity is through chromatin remodeling and methylation of the genome, while there are also recent data to suggest additional mechanisms, such as altered RNA processing and enhancer activity. Aberrant expression of lncRNA has been linked with various dis- ease processes, including cancer. One of the most well studied lncRNA, Hox Transcript Antisense Intergenic RNA (HO- TAIR), is one such lncRNA whose enhanced expression has been associated with carcinomas of the breast. In addition to reviewing the extensive research focused on HOTAIR expression and regulation of breast cancer through canonical path- ways, we will examine new studies that suggest the ability of HOTAIR to regulate microRNA (another type of non-cod- ing RNA) through direct binding inhibition, and how dysregulation of HOTAIR expression is relevant to breast cancer.

Keywords: HOTAIR, long non-coding RNA, cancer metastases, microRNA, non-coding RNA INTRODUCTION son lncRNAs are of particular interest is their similarity The discovery of genome mapping and the advancement to protein coding transcripts (Housman & Ulitsky, 2016; of sequencing technology within the past few decades Smith et al., 2014), generating discussion on the asso- KDVOHGWRWKHLGHQWL¿FDWLRQRIRQO\SURWHLQFRGLQJ ciation between the noncoding and coding world. One genes, correlating to less than 1% of the entire human ge- particular lncRNA, HOTAIR (Hox Transcript Antisense nome (Wilusz, Sunwoo, & Spector, 2009). Transcription- Intergenic RNA), is transcribed from the HOXC locus al analysis has revealed that while there are only 20,000 on chromosome 12 and is one of the main regulatory or- protein coding genes, over 90% of the human genome is chestrates of cellular activity (Rinn et al., 2007). HOTAIR transcribed into some sort of product (Wilusz et al., 2009). plays roles both in normal developmental processes and Genomic analyses revealed extensive networks involving cellular aberrancies, including cancer (Gupta et al., 2010; noncoding elements within the cell (Jia et al., 2010); typ- Rinn et al., 2007). This review will focus primarily on the LFDOO\FODVVL¿HGDVHLWKHUVPDOOQRQFRGLQJ51$V V51$  role of HOTAIR in gene regulation in both normal and or long noncoding RNAs (lncRNA) with many subtypes dysregulated cells, as well as general lncRNA biology. within each category. Noncoding RNAs were found to be involved in master regulatory programs in the cell includ- HOTAIR AS A LONG NON-CODING RNA ing apoptosis and cellular development. Small RNAs in- The ever growing and complex roles of lncRNAs in volved in RNA interference, such as miRNAs, have been cellular processes are far from being fully elucidated; extensively studied (reviewed in Alvarez-Garcia & Mis- however, it appears that many lncRNAs are able to ex- ka, 2005; Ambros, 2004); however, unlike small RNAs, ert multiple mechanisms to aid in regulatory programs long non-coding RNAs are larger in size, typically longer (Goff & Rinn, 2015). HOTAIR is known to direct gene than 200 nucleotides (Kung, Colognori, & Lee, 2013), and expression using many different modes of genom- are not highly conserved sequence-wise between species ic control. In our discussion of HOTAIR, we will em- (Diederichs, 2014; Novikova, Hennelly, & Sanbonmatsu, phasize its function in normal embryonic growth and 2013). Despite the lack of sequence conservation between how dysregulation of HOTAIR can promote cancer and species, lncRNAs are able to fold into extensive high or- cancer metastasis. To begin, we will decode the multi- der structures and motifs that are conserved in mammals farious labyrinth that is HOTAIR function to better un- (Diederichs, 2014). The ability of noncoding RNAs, spe- derstand the secrets behind lncRNA gene regulation. FL¿FDOO\OQF51$VWRDVVLVWLQFRPSOH[FHOOXODUSURJUDPV The biogenesis of HOTAIR is similar to that of a may be a result of the numerous secondary structures they normal protein coding mRNA transcript: the lncRNA is form (Mercer & Mattick, 2013; Novikova et al., 2013). polyadenylated (3’), spliced, and capped (5’) (Rinn et al., These higher order structures aid in regulatory functions 2007). This commonality of lncRNAs to be extensively (Goff & Rinn, 2015; Mercer & Mattick, 2013) and can processed like a protein coding gene creates more specu- provide localization signals (Zhang et al., 2014). One rea- ODWLRQDURXQGWKHLURULJLQDQGWKHLUVLJQL¿FDQFHLQWKHFHOO

41 Hammer et al. DOI 10.24049/aq.3.1.6

(Karapetyan, Buiting, Kuiper, & Coolen, 2013). HOTAIR such as development (da Rocha et al., 2014, p. 2; Tsai is known to be expressed from the HOXC gene locus et al., 2010). Beyond associating with protein complex- (Rinn et al., 2007), a member of the HOX gene cluster, es in the nucleus, HOTAIR is also able to function as a which is known to be involved in spatial development scaffold for ubiquitin ligases in the cytoplasm, aiding in of organisms and crucial for proper body organization WKHSURWHRO\VLVRIWDUJHWSURWHLQV gene expression regula- noncoding RNA has shown new insights into its role and tion required for proper development and correct cellular PHFKDQLVP+27$,5KDV¿YHYLDEOHLVRIRUPVRUVSOLFLQJ pattern organization (Rinn et al., 2007; Tsai et al., 2010). variants, that may be expressed at different levels in var- ious tissue types (Loewen, Jayawickramarajah, Zhuo, & HOTAIR IN EMBRYONIC PATTERNING Shan, 2014), while the full length transcript (Ensembl ID: The mammalian fetus begins its life as a single fertilized ENST00000424518) appears to be the predominant form. egg which quickly doubles into two and then again until it 7KHVLJQL¿FDQFHRI+27$,5LVRIRUPH[SUHVVLRQGLIIHU- reaches the blastocyst stage (Brown & Fabro, 1981); gene ences is currently unclear in both normal and disease states. expression can begin as early the four cell stage (Braude, Bolton, & Moore, 1988). It is during this time that crosstalk between noncoding and coding transcripts begins to weave the pattern that leads to fetal growth. Soon after, HOTAIR begins its expressive role during somite formation where it plays a pivotal part in proper embryonic progression in HPEU\RQLF¿EUREODVWV /LHWDO 7KHFRPSOH[LW\RI limb development and spatial arrangement require time VSHFL¿FJHQHWLFSURJUDPVLQYROYLQJPHWK\ODWLRQVWRFRQ- trol gene expression. As an organism grows in phyloge- netic intricacy, such as the transition from invertebrate to vertebrate, genetic control is expressed a great deal in the form of methylation of genes (Bird, 1995). It has become apparent that lncRNAs play a major role in this process; the ability of RNA to form extensive stem-loop structures and secondary motifs allows these molecules to associate Figure 1 The lncRNA, HOTAIR, regulates cell processes through and bind to protein domains as the orchestrators behind several molecular mechanisms. lncRNA, including HOTAIR, ex- many genomic operations (Mercer & Mattick, 2013). ert regulatory effects in both the nucleus and cytoplasm. Regula- tion of gene expression can be inhibitory, via chromatin remod- eling and methylation, or enhancing through reorganization of chromatin brining enhancer and promotor regions together (eRNA). Cytoplasmic regulation occurs through enhanced ubiquitin targeting guided by lncRNA, or by lncRNA acting as decoy molecules prevent- ing proper binding of proteins or other ncRNA to their target molecules.

While there are many mechanisms of action of ln cRNA, including both nuclear and cytoplasmic functions (Figure 1), the canonical mechanism of lncRNA action occurs via association with protein complexes within the QXFOHXVWRPHWK\ODWHVSHFL¿FUHJLRQVRQWDUJHWFKURPR- somes (Saxena & Carninci, 2011). The ability of lncRNAs to associate with chromatin remodeling complexes allows them to either silence or upregulate gene expression (re- viewed in Rinn & Chang, 2012), allowing lncRNAs to shape the human genome. LncRNAs, such as HOTAIR, are able to recruit large nuclear protein complexes that Figure 2 HOTAIR exerts chromosomal regulation in both cis and can methylate targeted gene regions to alter gene ex- trans. Following transcription and splicing, HOTAIR can associ- pression (Kaneko et al., 2014; Zhu, Rowley, Böhmdor- ate with the home chromosome 12 to regulate chromatin structure and availability for gene expression, though this mechanism is not fer, & Wierzbicki, 2013). Positive interactions between well understood. Conversely, HOTAIR can associate with PRC2 lncRNAs and these protein complexes, in which the ln- and LSD1/coREST/Rest protein complex, localize to the HOXD cRNA acts as a scaffold for the complex, enables them cluster on chromosome 2, and regulate expression via methylation. to silence genes and regulate major genetic programs,

42 Aquila - The FGCU Student Research Journal

The mechanism of HOTAIR stems from its ability to a recent development involving extensive noncoding act as a scaffold, bringing together two important protein networks. Understanding the role of HOTAIR in prop- complexes, the Polycomb Repressive Complex (PRC2) er function is essential in determining how it becomes DQG WKH O\VLQH VSHFL¿F GHPHWK\ODVH FRPSOH[ /6'  dysregulated in cancer and disease progression, and CoREST/REST (Tsai et al., 2010). The 5’ end of HOTAIR the potential of lncRNA as future therapeutic targets. binds to PRC2 and the 3’ end binds to LSD1/CoREST/ REST, allowing HOTAIR to mediate methylation of target HOTAIR IN CELLULAR ABERRANCY genes to induce silencing (Tsai et al., 2010). Interestingly, Abnormal regulation of cellular processes can lead to dis- while HOTAIR is expressed from the HOXC cluster on ease progression and cancerous growth. When cell cycle chromosome 12, it does not drive major gene regulation lo- control is lost, the cell relinquishes its identity and evolves FDOO\,QVWHDG+27$,5ZDVLGHQWL¿HGDVWKH¿UVWOQF51$ into a cancerous cell (Nowell, 1976). The balance between to alter gene expression in trans (Rinn et al., 2007) (Figure apoptosis/cell death and uncontrolled proliferation is lost 2). HOTAIR exerts cis-regulatory control on the HOXC in these cells. LncRNAs are not bystanders in this dichoto- locus of chromosome 12 demonstrating local gene silenc- my; often, they are malignant drivers of this loss of control ing, although the mechanism behind this is not well un- (Prensner & Chinnaiyan, 2011). HOTAIR is no exception, derstood. Unlike many other lncRNA, however, HOTAIR as increased expression is associated with poorer progno- can also act in trans, as it moves dynamically from the ses and cellular dysregulation (Kogo et al., 2011). The same HOXC locus on chromosome 12, to the HOXD locus on mechanisms by which HOTAIR regulates normal embry- chromosome 2 (Axelsdottir, 2014). While the mechanism onic development are involved in cellular dysfunction and has yet to be fully elucidated, it is clear that HOTAIR as- uncontrolled growth (Gupta et al., 2010) when HOTAIR sociates with both PRC2 and LSD1/CoREST/REST. This expression is altered to abnormal levels (Figure 3). While associated complex of protein and RNA is then shuttled HOTAIR can direct many aberrant processes that lead to from chromosome 12 to chromosome 2 to regulate HOXD FDQFHUZHZLOOVSHFL¿FDOO\IRFXVRQLWVDELOLW\WRUHSUR- H[SUHVVLRQ E\ SURPRWLQJ KLVWRQH PRGL¿FDWLRQ DQG WUDQ- gram nuclear organization, promote epithelial-to-mesen- scriptional silencing. The ability of HOTAIR to alter a dis- chymal transition (EMT), and inhibit microRNA function. tant gene expression in trans reveals a novel mechanism of regulation that allows HOTAIR to affectively drive gene silencing on a different chromosome (Tsai et al., 2010). The discovery of HOTAIR’s association with a syn- tenic loci, a highly conserved region of the HOXC lo- cus among vertebrates (Rinn et al., 2007), led to further probing of its unique mechanism. Due to its localization in a homeobox domain, HOTAIR has been implicated in a wide range of developmental regulation from skin cell array to limb formation (Li et al., 2013; Rinn et al., 2007). Without the scaffolding function of HOTAIR, embryos would be developmentally stunted in severe ways; limbs would not grow correctly and adult skin would be drasti- cally altered, most likely resulting in the termination of the somite at an early stage (Li et al., 2013). In extreme cases with complete absence of HOTAIR, homeosis, a transformation of one organ into another due to improper Figure 3. HOTAIR serves roles in both normal development and can- JHQHVLOHQFLQJDWVSHFL¿FPRPHQWVLQGHYHORSPHQW /LHW FHUSURJUHVVLRQ,QVXI¿FLHQWH[SUHVVLRQRI+27$,5LQHPEU\RQLFVWDJ- HVLVGHWULPHQWDOOHDGLQJWRGH¿FLHQFLHVLQFHOOSDWWHUQLQJ'HSHQGLQJ DO   FDQ RFFXU 6SHFL¿FDOO\ +27$,5LV PRVW LQ- on the stage of development at which HOTAIR expression becomes volved in lumbosacral region and forelimbs development. dysregulated, loss of HOTAIR can be lethal to the embryo. As cells While HOTAIR is crucial in embryonic development, it become more differentiated, HOTAIR levels decrease. Aberrant ex- also aids in determining the placement of mature skin pression of HOTAIR in differentiatied epithelial cells leads to rever- sion to a less differentiated stem-like state, with increased EMT gene cells and maintaining their coherence, termed positional expression, and disregulated processes associated with cancer. identity (Li et al., 2013). This way HOTAIR plays roles crucial to both developing fetuses and mature organisms. Its ability to methylate and control HOX genes en- The impact HOTAIR has on development acts as dows HOTAIR with a novel mechanism to control gene a double-edged sword as it makes HOTAIR a potential expression; once HOTAIR becomes overexpressed, it re- player in aberrant cellular processes, such as cancer. directs the polycomb repressor proteins and reinstitutes 7KHLGHQWL¿FDWLRQRI+27$,5DVDQRQFRJHQLFOQF51$ embryonic programming in differentiated cells (Gup- has led to many new insights into the mechanisms that ta et al., 2010). By doing this, HOTAIR successfully control cancer progression and metastasis, including brings a cancerous cell to a nuclear organization similar

43 Hammer et al. DOI 10.24049/aq.3.1.6 to that of an embryonic cell; in such cases, HOTAIR has et al., 2014). An important regulator of EMT, the SNAIL been shown to alter a cancerous breast cell so much that protein, is also shown to associate with HOTAIR in the 35& SUR¿OH LQ WKH QXFOHXV PRUH FORVHO\ UHVHPEOHV DQ nucleus and direct the methylation of targets to further HPEU\RQLF ¿EUREODVW WKDQ D GLIIHUHQWLDWHG EUHDVW HSLWKH- promote EMT; again, in this situation HOTAIR acts as a lial cell (Gupta et al., 2010). With the changed nuclear scaffold bringing together SNAIL and the EZH2 subunit status, important tumor suppressors become methylated of PRC2 for targeted methylation (Battistelli et al., 2016). and inactivated; genes such as HOXD10, progesterone RNAs are able to negatively interact with each other receptor (PGR), and protocadherin (PCDH) are no longer through formation of the RNA-induced silencing complex able to protect the cell from entry into the cell cycle (RISC); this interaction is commonly known as RNA in- (Kogo et al., 2011). Correlating with an overexpression terference. RNA interference is prototypically thought to of HOTAIR, protein complexes of PRC2 are also upreg- be between microRNAs and mRNA transcripts (reviewed ulated in a cancerous cell (Kogo et al., 2011). The way in Filipowicz, Bhattacharyya, & Sonenberg, 2008); how- that HOTAIR is able to reprogram nuclear organization ever, negative interactions between small RNAs and in cancer is reminiscent of an embryonic cell (Gupta et coding transcripts, are not the only applications of RNA al., 2010) creating speculation that it may be involved induced silencing. Termed competing RNAs, crosstalk in the formation of cancer stem cells (CSCs) (Kogo et between noncoding RNAs has become one of the fore- al., 2011). Indeed, pathway analysis and in vitro studies fronts of modern RNA research (Salmena, Poliseno, Tay, have determined a positive correlation between HOTAIR .DWV 3DQGRO¿ 51$51$QHWZRUNVKDYHEHHQ DQG FDQFHU VWHPQHVV < /LX HW DO   ,W KDV EHHQ LGHQWL¿HGLQPDQ\FDQFHUVOHDGLQJWRDQLQFUHDVHLQPH- shown previously that the polycomb group proteins are tastases and epithelial-to-mesenchymal (EMT) transition involved in CSC formation, so it follows that HOTAIR, .DUUHWK 3DQGRO¿ ,QSDUWLFXODUPDQ\OQF51$V a regulator of PRC2, may also be involved in CSC gene- act as molecular sponges, binding microRNA, and thus sis (Valk-Lingbeek, Bruggeman, & van Lohuizen, 2004) preventing microRNA targeting of oncogenic transcripts One of the factors closely associated with metastasis is (G. Guo et al., 2015; X. Liu et al., 2014; Wang et al., 2010) the progression of an epithelial cell to a mesenchymal (Figure 4). Competitive endogenous RNA (ceRNA) net- cell, also known as the epithelial-to-mesenchymal transi- ZRUNVKDYHIXUWKHUHGWKHLGHQWL¿FDWLRQDQGPHFKDQLVPRI tion (EMT). This transformation causes an epithelial cell oncogenic lncRNAs, such as HOTAIR, that drive cancer to lose its cell-to-cell adhesive property, allowing cells to metastasis (X. Liu et al., 2014). These networks are par- become invasive, a prerequisite to metastatic spreading ticularly important in cancer progression because they can RIFDQFHURXVFHOOVWRGLVWDQWWLVVXHV

Figure 4 HOTAIR acts as a molecular decoy for microRNA. microRNA regulate gene expression by binding target mRNA transcripts in the cytoplasm and preventing translation of the gene and/or targeting the mRNA transcript for degradation. HOTAIR can also bind microRNA through complementary base pairing, preventing the bound microRNA from binding target mRNA sequences. This leads to dysregulated increases in target gene expression.

44 Aquila - The FGCU Student Research Journal allows the unhindered expression of the HER2 oncogene better help researchers in their quest to understand how by binding microRNA 331-3p and preventing it from sup- HOTAIR could potentially lead to a cancerous state. As pressing HER2 (X. Liu et al., 2014). LncRNAs in this ca- it has been shown, lncRNAs are far from a byproduct pacity are also referred to as molecular sinks or “sponges” of transcription as they were once thought; instead, they IRUPLFUR51$V 7D\5LQQ 3DQGRO¿ 0DQ\DV- have taken on a new role in shaping the human genome. pects of the ceRNA mechanism are yet to be revealed but this area shows promise and elucidates a new role for ln- WORKS CITED cRNAs in regulatory control of non-coding RNA networks. Alvarez-Garcia, I., & Miska, E. A. (2005). MicroR- NA functions in animal development and hu- FUTURE PERSPECTIVES man disease. Development, 132(21), 4653–4662. 5HFHQW¿QGLQJVKDYHEURXJKWOQF51$VWRWKHIRUHIURQWRI Ambros, V. (2004). The functions of animal mi- molecular genetics where they have been shown to be cru- croRNAs. Nature, 431(7006), 350–355. cial regulators of genomic programs and gene expression. Axelsdottir, E. (2014). The RNA HOTAIR Pro- With the discovery of ribozymes, a new view of life was motes Chromatin Alteration in Can- created with RNA at the center, termed the “RNA World” FHU -RXUQDO RI chromosomes or of distance ones (Naga- development. Nature, 332(6163), 459–461. no & Fraser, 2011). The aforementioned integral regulator, Brown, N. A., & Fabro, S. (1981). Quantitation of rat HOTAIR, is able to control many crucial cellular programs embryonic development in vitro: a morpholog- through association with nuclear complexes. Setting the ical scoring system. Teratology, 24(1), 65–78. landscape for what will be a future revolution in the way Chen, X., Li, N., & Ellington, A. D. (2007). Ri- gene expression is understood, lncRNAs such as HOTAIR bozyme catalysis of metabolism in the RNA will provide new insight into the world of genomics. world. Chemistry & Biodiversity, 4(4), 633–655. Starting with a narrow focus, such as the details in the da Rocha, S. T., Boeva, V., Escamilla-Del-Arenal, mechanism of one lncRNA, we hope to open up novel M., Ancelin, K., Granier, C., Matias, N. R., & pathways to understanding other similar lncRNAs. By Picard, C. (2014). Jarid2 is implicated in the ini- VXPPDUL]LQJ UHFHQW ¿QGLQJV LQ WKH UHJXODWRU\ UROHV RI tial Xist-induced targeting of PRC2 to the inactive HOTAIR, we can speculate that in the future some of X chromosome. Molecular Cell, 53(2), 301–316. these mechanisms might be able to be generalized to new- Diederichs, S. (2014). The four dimensions of noncoding ly discovered noncoding RNAs. In this way, we hope to RNA conservation. Trends in Genetics, 30(4), 121–123. eventually archive detailed mechanisms of more lncRNAs Filipowicz, W., Bhattacharyya, S. N., & Sonenberg, to categorize them into groups of similar regulatory N. (2008). Mechanisms of post-transcription- function. Doing this will allow easy access to informa- al regulation by microRNAs: are the answers in tion and promote further exploration in the lab. Detail- sight? Nature Reviews Genetics, 9(2), 102–114. ing the mechanisms of lncRNA action we can anticipate Furió-Tarí, P., Tarazona, S., Gabaldón, T., Enright, a future where lncRNAs will be grouped based on their A. J., & Conesa, A. (2016). spongeScan: A web associations with particular nuclear machinery, allowing for detecting microRNA binding elements in ln- for a deeper understanding of how they could potential- cRNA sequences. Nucleic Acids Research, gkw443. ly work in concert to conduct genomic programs. Due to Goff, L. A., & Rinn, J. L. (2015). Linking RNA biology the complexity of HOTAIR, it may not be an abstract as- to lncRNAs. Genome Research, 25(10), 1456–1465. sumption to speculate that HOTAIR could work in series Guo, G., Kang, Q., Zhu, X., Chen, Q., Wang, X., with other nuclear lncRNAs. Reviewing the current liter- &KHQ <  &KHQ 5   $ ORQJ QRQFRGLQJ ature on lncRNAs will enable researchers to extrapolate RNA critically regulates Bcr-Abl-mediated cellu- further associations RNA may make to promote cellular lar transformation by acting as a competitive en- SURFHVVHV)XUWKHUEHFDXVH+27$,5LVDQLGHQWL¿HGRQ- dogenous RNA. Oncogene, 34(14), 1768–1779. cogenic lncRNA, understanding its mechanism from both *XR ; *DR / :DQJ<&KLX ' . :DQJ 7  a developmental and aberrant regulatory standpoint will 'HQJ<  $GYDQFHVLQORQJQRQFRGLQJ51$V

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Wu, Z.-H., Wang, X.-L., Tang, H.-M., Jiang, T., Chen, Scaffold function of long non-coding RNA HOTAIR - /X 6 

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