Long intervening noncoding RNAs (lincRNAs) in vertebrate development
KeywordslincRNAs, regulatory RNAs, zebrafish development, brain development, genomics
The human genome encodes thousands of long intervening noncoding RNAs (lincRNAs) that have been called the “dark matter” of the genome because little is known about their functions. Our lab studies the roles of lincRNAs in embryonic development using zebrafish as a tool. We perturb selected lincRNAs in fish, observe how loss of a lincRNA affects embryonic development and then replace it with the human variant of the same lincRNA. Two lincRNAs that we looked at restore proper development in zebrafish, indicating that these non-coding RNAs have equivalent functions in humans and fish.
To understand developmental functions of lincRNAs, we have identified over 550 lincRNAs in zebrafish. We previously demonstrated that two novel lincRNAs, megamind and cyrano, are required for proper embryonic development, in particular for brain morphogenesis and neurogenesis (Figure 1) (Ulitsky*, Shkumatava* et al., Cell, 2011). Remarkably, the functions of megamind and cyrano are conserved between zebrafish and mammals, despite rapid evolution that has resulted in little sequence conservation. Our goal is to determine the functions of lincRNAs in vertebrate development and identify molecular mechanisms they employ to carry out these functions.
Developmental functions of lincRNAs
The majority of lincRNAs are expressed in specific regions of the developing nervous system in zebrafish embryos (Figure 2). Thus, we are particularly interested in the roles lincRNAs play in establishing cellular complexity in CNS. We are exploring lincRNA functions by manipulating their gene expression and analyzing phenotypic consequences of lincRNA perturbations in zebrafish embryos. We are focusing on lincRNAs that, like megamind and cyrano, have sequence conservation to mammals.
|Molecular and biochemical mechanisms of lincRNAs action |
To unravel how lincRNAs regulate embryonic development, we are investigating the molecular and biochemical mechanisms of lincRNA action by determining their interaction partners and downstream targets. We use two complementary systems, zebrafish embryos and mammalian cell culture, to dissect cellular roles of lincRNAs with important biological functions, such as megamind and cyrano. The powerful combination of zebrafish genetics, molecular and cellular biology, genome-wide approaches and bioinformatics allows us to address whether lincRNAs employ common mechanisms of action similar to other noncoding RNAs such as microRNAs.
The origin and evolution of vertebrate lincRNA genes
Year of publication: 2011
Ulitsky I*, Shkumatava A*, Jan C, Sive H, Bartel DP. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution.
* denotes equally contributing authors
Year of publication: 2009
Shkumatava A, Stark A, Sive H and Bartel DP. Coherent but overlapping expression of miRNAs and their targets during vertebrate development.
Genes Dev. 15;23(4):466-81.