Noncoding RNAs and chromatin structure
A major surprise over the last ten years has been the discovery of many diverse roles of noncoding RNAs.
Several families of small (21-25 nt) RNAs mediate gene silencing through RNAi-like mechanisms or translational control.
Noncoding RNAs are produced in most imprinted loci in mammals, although their functions remain a mystery. Larger RNAs such as
Xist in mammals and roX in flies paint entire X chromosomes to somehow target chromatin remodeling enzymes to
the correct chromosome. My research program exploits the many genetic, molecular, and cytological advantages of Drosophila
to understand how the roX RNAs direct the dosage compensation machinery to the male X chromosome.
Flies have two different roX RNAs. The genes producing roX1 and roX2 both map to the X chromosome,
and their RNA products "paint" the 21 Mbp euchromatic portion of the male X in a reproducible pattern of hundreds of bands
when complexed with the 5 known MSL proteins. Some of the MSL proteins are histone modifying enzymes which alter the chromatin
architecture allowing a two-fold increase in transcription from thousands of unrelated genes linked on the male X chromosome.
One of the primary functions of the roX RNA seems to be targeting these chromatin remodeling enzymes to the correct
sites in the genome. The two roX RNAs are very different in size (3.7 vs. 0.6 kb) and have almost no primary sequence
in common, and yet are functionally redundant. Males can survive with only roX1 or only roX2 but die if both
genes are mutated. Females are unaffected my mutations in roX genes or msl genes because they do not
hypertranscribe their two X chromosomes.
We are currently testing a model that postulates that the MSL complex spreads epigenetically from sites of roX
transcription. We now understand the factors that control local spreading along a chromosome, but the question being asked is
whether this serves to deliver the MSL complex to target genes along the X, or perhaps some other autoregulatory function
controlling roX transcription.
Selected Publications
Kelley RL, Meller VH, Gordadze PR, Roman G, Davis RL, Kuroda MI (1999) Epigenetic
spreading of the Drosophila dosage compensation complex from roX RNA genes into flanking
chromatin. Cell 98:513-522.
Meller VH, Gordadze PR, Park Y, Chu X, Stuckenholz C, Kelley RL, Kuroda MI (2000) Ordered
assembly of roX RNAs into MSL complexes on the dosage-compensated X chromosome in Drosophila.
Current Biology 10:136-143.
Kageyama Y, Mengus G, Gilfillan G, Kennedy HG, Stuckenholz C, Kelley RL, Becker PB, Kuroda MI (2001)
Association and spreading of the Drosophila dosage compensation complex from a
discrete roX chromatin entry site. EMBO Journal 20:2236-2245.
Park Y, Kelley RL, Oh H, Kuroda MI, Meller VH (2002) Extent of chromatin spreading determined by
roX RNA recruitment of MSL proteins. Science 298:1620-1623.
Kelley RL, Kuroda MI. (2003) The Drosophila roX1 RNA gene can overcome silent chromatin by
recruiting the male-specific lethal dosage compensation complex. Genetics 164:565-574.
Kelley RL (2004) Path to equality strewn with roX. Developmental Biology 269:18-25.
Contact Information
- Richard L. Kelley, Ph.D.
- Department of Molecular and Cell Biology,
- Department of Molecular and Human Genetics
- Baylor College of Medicine
- One Baylor Plaza T734
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-4526
- Fax: (713) 798-8515
- E-mail: rkelley@bcm.tmc.edu
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