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Abstract:
Alternative messenger RNA splicing is the main reason that vast
mammalian proteomic complexity can be achieved with a limited
number of genes. Splicing is physically and functionally coupled to
transcription, and is greatly affected by the rate of transcript
elongation
1–3
. As the nascent pre-mRNA emerges from transcrib-
ing RNA polymerase II (RNAPII), it is assembled into a messenger
ribonucleoprotein (mRNP) particle; this is the functional form of
the nascent pre-mRNA and determines the fate of the mature tran-
script
4
. However, factors that connect the transcribing polymerase
with the mRNP particle and help to integrate transcript elongation
with mRNA splicing remain unclear. Here we characterize the
human interactome of chromatin-associated mRNP particles.
This led us to identify deleted in breast cancer 1 (DBC1) and
ZNF326
(
which we call ZNF-protein interacting with nuclear
mRNPs and DBC1 (ZIRD)) as subunits of a novel protein
complex
—
named DBIRD
—
that binds directly to RNAPII. DBIRD
regulates alternative splicing of a large set of exons embedded in
(
A
1
T)-rich DNA, and is present at the affected exons. RNA-
interference-mediated DBIRD depletion results in region-specific
decreases in transcript elongation, particularly across areas encom-
passing affected exons. Together, these data indicate that the
DBIRD complex acts at the interface between mRNP particles
and RNAPII, integrating transcript elongation with the regulation
of alternative splicing
