Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

REGULATION OF GENE EXPRESSION BY NONCODING RNAs
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Long Noncoding RNAs Have Diverse Functions in the Cell
In this and the preceding chapters, we have seen that noncoding RNA molecules
have many functions in the cell. Yet, as is the case with proteins, there remain
many noncoding RNAs whose function is still unknown. Many RNAs of unknown
function belong to a group known as long noncoding RNA (lncRNA). These are
arbitrarily defined as RNAs longer than 200 nucleotides that do not code for protein.
As methods have improved for determining the nucleotide sequences of all
the RNA molecules produced by a cell line or tissue, the sheer number of lncRNAs
(an estimated 8000 for the human genome, for example) came as a surprise to scientists.
Most lncRNAs are transcribed by RNA polymerase II and have 5ʹ caps and
poly-A tails, and, in many cases, they are spliced. It has been difficult to annotate
lncRNAs because low levels of RNA are now known to be made from 75% of the
human genome. Most of these RNAs are thought to result from the background
“noise” of transcription and RNA processing. According to this idea, such nonfunctional
RNAs provide no fitness advantage or disadvantage to the organism
and are a tolerated by-product of the complex patterns of gene expression that
need to be produced in multicellular organisms. For these reasons, it is difficult to
estimate the number of lncRNAs that are likely to have a function in the cell and to
distinguish them from the background transcription.
We have already encountered a few lncRNAs, including the RNA in telomerase
(see Figure 5–33), Xist RNA (see Figure 7–52), and an RNA involved in imprinting
(see Figure 7–49). Other lncRNAs have been implicated in controlling the enzymatic
activity of proteins, inactivating transcription regulators, affecting splicing
patterns, and blocking translation of certain mRNAs.
In terms of biological function, lncRNA should be considered a catch-all phrase
encompassing a great diversity of functions. Nevertheless, there are two unifying
features of lncRNAs that can account for their many roles in the cell. The first is
that lncRNAs can function as scaffold RNA molecules, holding together groups of
proteins to coordinate their functions (Figure 7–79A). We have already seen an
example in telomerase, where the RNA molecule holds together and organizes
protein components. These RNA-based scaffolds are analogous to protein scaffolds
we discussed in Chapter 3 (see Figure 3–78) and Chapter 6 (see Figure 6–47).
RNA molecules are well suited to act as scaffolds: small bits of RNA sequence,
often those portions that form stem-loop structures, can serve as binding sites
for proteins, and these can be strung together with random sequences of RNA
in between. This property may be one reason that lncRNAs show relatively little
primary-sequence conservation across species.
The second key feature of lncRNAs is their ability to serve as guide sequences,
binding to specific RNA or DNA target molecules through base-pairing. By doing
so, they bring proteins that are bound to them into close proximity with the DNA
Figure 7–79 Roles of long noncoding
RNA (lncRNA). (A) lncRNAs can serve as
scaffolds, bringing together proteins that
function in the same process. As described
in Chapter 6, RNAs can fold into specific
three-dimensional structures that are often
recognized by proteins. (B) In addition to
serving as scaffolds, lncRNAs can, through
formation of complementary base pairs,
localize proteins to specific sequences on
RNA or DNA molecules. (C) In some cases,
lncRNAs act only in cis, for example,
when the RNA is held in place by RNA
polymerase (top). Other lncRNAs, however,
diffuse from their sites of synthesis and
therefore act in trans.
controls transcription of
genes on same chromosome
ACTS IN CIS
(A)
IncRNA
IncRNA
chromosome A
RNA polymerase
controls transcription of
genes on other chromosomes,
ACTS IN
TRANS
IncRNA
(B)
RNA
DNA
(C)
chromosome A
chromosome B