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Annu. Rev. Biochem. 2012.81:61-64. Downloaded from www.annualreviews.org

Joan W. Conaway1,2
1
Stowers Institute for Medical Research, Kansas City, Missouri 64110;
email: JLC@stowers.org
2
Department of Biochemistry and Molecular Biology, Kansas University Medical Center,
Kansas City, Kansas 66160

Annu. Rev. Biochem. 2012. 81:61–64 Keywords

First published online as a Review in Advance on
March 8, 2012
The Annual Review of Biochemistry is online at
biochem.annualreviews.org
This article’s doi:
10.1146/annurev-biochem-090711-093103
Copyright  c 2012 by Annual Reviews.
All rights reserved
0066-4154/12/0707-0061$20.00
DNA methylation, noncoding RNA, histone modification, RNA
polymerase II, elongation
Abstract
Transcriptional regulation in eukaryotes depends on a complex network
of interactions between RNA polymerases and a host of transcription
factors and coregulators that control their activity during transcrip-
tion initiation and elongation. Among these are an enormous variety of
enzymes and proteins that modulate chromatin structure via changes
in DNA methylation, histone modifications, and nucleosome location.
This volume of the Annual Review of Biochemistry contains a set of four re-
views addressing the interplay between mechanisms that regulate DNA
methylation, chromatin structure, and transcription.

61
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ARI 3 May 2012 7:30
The development of a multicellular organism
from a fertilized egg requires proper execution
of a transcription program that results in syn-
thesis of many thousands of messenger RNAs
(mRNAs), at exactly the right time, in the right
set of cells, and in the right amount. Misreg-
ulation of the transcriptional program is as-
sociated not only with developmental defects
but also with many disease states. Accordingly,
major goals of research over the past several
decades have been to define the components of
the transcriptional regulatory apparatus and to
work out the details of how they function to-
gether to attain the exquisitely precise control
of the transcription output required for normal
development and function. This work has led
over time to the revelation that regulation of eu-
karyotic mRNA synthesis is a multi-tiered pro-
cess governed by an intricate interplay between
chromatin structure and the RNA polymerase
II (Pol II) transcription machinery. Chromatin
structure is controlled locally, at the gene level,
and globally through the action of a withering
collection of enzymes and proteins that regulate
both the methylation status of chromosomal
DNA and the distribution and modification of
nucleosomes along it. Like the cell’s machinery
for regulating chromatin structure, the RNA
Pol II transcription machinery is elaborate and
composed of a large collection of transcription
factors that control not only transcript initi-
ation, but also transcript elongation through
chromatin. This volume of the Annual Review
of Biochemistry includes four articles addressing
the interplay between chromatin structure and
RNA Pol II transcription.
At its most fundamental level, the transcrip-
tion of a gene by any RNA polymerase can
be described in terms of a transcription cycle
that can be divided into multiple, mechanisti-
cally distinct stages. In the first stage, the en-
zyme must be able to identify, bind to, and
initiate transcription correctly at promoters in
the background of the large amount of nonpro-
moter DNA in the cell. Having initiated tran-
scription, an RNA polymerase must elongate
the nascent transcript until it reaches the gene’s
3 end, a process that in higher eukaryotes can
62 Conaway
require it to traverse hundreds of kilobases be-
fore it terminates transcription and is released
from the gene.
For many years, it was assumed that the
majority of Pol II transcriptional regulation
was accomplished at the earliest stages of the
transcription cycle by processes that affect
the efficiency with which the enzyme is re-
cruited to promoters and initiates transcrip-
tion; however, hints that transcript elongation
could also be a key site for regulation came
from evidence that most Pol II elongation in
vitro or in cells is sensitive to inhibition by
the protein kinase inhibitor 5,6-dichloro-1-β-
D-ribofuranosylbenzimidazole or DRB (1, 2).
Subsequently, seminal studies of heat shock
gene expression in Drosophila and of c-myc, c-
fos, and other oncogenes in human cells re-
vealed that transcription of some genes can
be regulated by promoter-proximal pausing
in which Pol II pauses shortly after initiat-
ing transcription and is released into produc-
tive elongation only upon gene activation (3–
5). Over the next decade or so, biochemical
studies identified a collection of transcription
elongation factors, including negatively acting
factors such as DRB sensitivity-inducing fac-
tor (DSIF) and the negative elongation factor
(NELF), which induce transcriptional pausing,
and positively acting factors, such as the pro-
tein kinase P-TEFb and eleven-nineteen lysine
rich in leukemia (ELL), which promote effi-
cient elongation. With the advent of genome-
wide methods for measuring nascent transcript
synthesis as well as the location of Pol II and
elongation factors on chromatin, it has become
clear that control at the level of transcript elon-
gation is a general feature of Pol II transcription
and plays a critical role in development and dis-
ease. In their review, entitled “RNA Polymerase
II Elongation Control,” Zhou and colleagues
(6) discuss our current understanding of the
mechanisms and transcription factors that con-
trol transcript elongation and associated pro-
cesses, such as RNA capping, splicing, and
polyadenylation.
In eukaryotic cells, chromosomal DNA is
packaged into arrays of nucleosomes, each of
 BI81CH03-Conaway ARI 3 May 2012 7:30
which contains ∼146 bp of DNA wrapped
around a histone octamer containing two copies
each of histones H2A, H2B, H3, and H4 (7).
These arrays are, in turn, folded into chro-
matin fibers made up of higher-order nucleo-
somal structures, allowing the several meters
of DNA that make up the human genome to
fit into nuclei with diameters of just a few mi-
crons. Although this compaction presents a se-
rious impediment to the RNA Pol II transcrip-
tion machinery, as well as to enzymes involved
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in other nuclear processes such as DNA repli-
cation and repair, it also provides remarkable
opportunities for gene regulation. Indeed, it is
Annu. Rev. Biochem. 2012.81:61-64. Downloaded from www.annualreviews.org
now clear that establishment and maintenance
of distinct patterns of gene expression in differ-
ent cell lineages are due in significant part to
epigenetic mechanisms that involve alterations
in chromatin structure driven in part by post-
translational modifications of histones and by
DNA methylation.
Regions of transcriptionally silenced
chromosomal DNA are enriched in CpG
dinucleotides containing cytosine residues
methylated at position 5 (8). In addition, the
chromatin of silenced regions contains high
levels of histone H3 dimethylated on lysine 9
(H3K9me2) and histone H3 trimethylated on
lysine 27 (H3K27me3) (9). In contrast, tran-
scriptionally active regions are associated with
hypomethylated DNA and with chromatin
with a different constellation of histone marks,
including histone H4 trimethylated on lysine
4 (H3K4me3) (9). Two reviews in this series,
“Programming of DNA Methylation Patterns,”
by Cedar & Bergman (10), and “The COM-
PASS Family of Histone H3K4 Methylases:
Mechanisms of Regulation in Development
and Disease Pathogenesis,” by Shilatifard (11),
review our current understanding of how these
epigenetic marks are established, maintained,
and function to control chromatin structure
and gene regulation.
In the final review in the series, “Genome
Regulation by Long Noncoding RNAs,” Rinn
& Chang (12) describe the identification
and functional analysis of a large set of long
noncoding RNAs (lncRNAs), at least some of
www.annualreviews.org • Chromatin, Epigenetics, and Transcription
which are proving to have roles in establishing
gene expression patterns important for stem
cell maintenance, cell fate determination dur-
ing development, and diseases such as cancer.
Until recently, it was thought that the vast ma-
jority of higher eukaryotic genomes are made
up of nontranscribed, so-called junk DNA that
lacks known protein coding sequences and has
no clear function. With the advent of high-
throughput methods for analyzing the entire
population of RNAs present in a given cell type,
however, it has become clear that a much larger
fraction of the genome is transcribed than
previously appreciated. Indeed, mammalian
cells express thousands of lncRNAs that are
encoded by previously unannotated regions of
the genome. That these lncRNAs often exhibit
sequence conservation across species suggested
that they have some function linked to their
structures (13, 14), and the challenges are now
to determine which of them contribute to
regulatory processes and how. In their review,
Rinn & Chang discuss emerging evidence that
lncRNAs can assemble into ribonucleoprotein
complexes and contribute to gene regulation
by mechanisms almost as diverse as those
employed by more conventional protein
regulators. Some lncRNAs serve as decoys
that mimic the DNA-binding sites of tran-
scriptional regulators and prevent them from
binding to their normal targets in promoter
DNA. Among these are the lncRNA Gas5,
which binds the the glucocorticoid receptor,
and an another called PANDA, which binds the
transcription factor NF-Y. Others can serve as
scaffolds or adapters to promote interactions
between multiple proteins or protein com-
plexes that regulate chromatin structure. For
example, an lncRNA called HOTAIR can bind
to both the histone H3 K27 methyltransferase
polycomb repressive complex 2 (PRC2) and the
histone H3 K4 demethylase LSD1-CoREST
to coordinate a repressive chromatin methy-
lation state. In addition, lncRNAs can serve
as guides that target their protein partners to
specific chromosomal locations, much like the
DNA-binding domain of a sequence-specific
DNA-binding protein. Thus, HOTAIR as well
63
 BI81CH03-Conaway ARI 3 May 2012 7:30

as a host of other lncRNAs have been shown
to bind PRC2, and in several cases, these have
been shown to contribute to PRC2 recruitment
and histone H3K27 methylation at specific
loci.
A few decades ago, we knew virtually noth-
ing about the the enzymes and proteins that co-
ordinate epigenetic modifications of chromatin
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and DNA with transcription or about how their
functions, and malfunctions, contribute to nor-
mal development and disease. Taken together,
these four reviews highlight just how much has
been learned. But as they also make clear, each
new answer raises new and unexpected ques-
tions, and research in this area should be fruitful
for many years to come.

DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
Annu. Rev. Biochem. 2012.81:61-64. Downloaded from www.annualreviews.org

be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENT
The author thanks Ronald C. Conaway for helpful suggestions during the preparation of this
introduction.

LITERATURE CITED
1. Tamm I, Kikuchi T. 1979. Early termination of heterogeneous nuclear RNA transcripts in mammalian
cells: accentuation by 5,6-dichloro 1-beta-D-ribofuranosylbenzimidazole. Proc. Natl. Acad. Sci. USA
76:5750–54
2. Zandomeni R, Bunick D, Ackerman S, Mittleman B, Weinmann R. 1983. Mechanism of action of DRB.
III. Effect on specific in vitro initiation of transcription. J. Mol. Biol. 167:561–74
3. Bentley DL, Groudine M. 1986. A block to elongation is largely responsible for decreased transcription
of c-myc in differentiated HL60 cells. Nature 321:702–6
4. Fort P, Rech J, Vie A, Piechaczyk M, Bonnieu A, et al. 1987. Regulation of c-fos gene expression in
hamster fibroblasts: initiation and elongation of transcription and mRNA degradation. Nucleic Acids Res.
15:5657–67
5. Rougvie AE, Lis JT. 1988. The RNA polymerase II molecule at the 5 end of the uninduced hsp70 gene
of D. melanogaster is transcriptionally engaged. Cell 54:795–804
6. Zhou Q, Li T, Price DH. 2012. RNA polymerase II elongation control. Annu. Rev. Biochem. 81:119–43
7. Kornberg RD. 1977. Structure of chromatin. Annu. Rev. Biochem. 46:931–54
8. Yisraeli J, Szyf M. 1984. Gene methylation patterns and expression. In DNA Methylation: Biochemistry and
Biological Significance, ed. A Razin, H Cedar, AD Riggs, pp. 352–70. New York: Springer-Verlag
9. Li B, Carey M, Workman JL. 2007. The role of chromatin during transcription. Cell 128:707–19
10. Cedar H, Bergman Y. 2012. Programming of DNA methylation patterns. Annu. Rev. Biochem. 81:97–117
11. Shilatifard A. 2012. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in
development and disease pathogenesis. Annu. Rev. Biochem. 81:65–95
12. Rinn JL, Chang HY. 2012. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81:145–66
13. Ponjavic J, Ponting CP, Lunter G. 2007. Functionality or transcriptional noise? Evidence for selection
within long noncoding RNAs. Genome Res. 17:556–65
14. Guttman M, Amit I, Garber M, French C, Lin MF, et al. 2009. Chromatin signature reveals over a
thousand highly conserved large non-coding RNAs in mammals. Nature 458:223–27

64 Conaway
 BI81-FrontMatter ARI 9 May 2012 7:26

Annual Review of
Biochemistry
Contents Volume 81, 2012

Preface
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Preface and Dedication to Christian R.H. Raetz

JoAnne Stubbe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p pxi
Annu. Rev. Biochem. 2012.81:61-64. Downloaded from www.annualreviews.org

Prefatories
A Mitochondrial Odyssey
Walter Neupert p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
The Fires of Life
Gottfried Schatz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p34

Chromatin, Epigenetics, and Transcription Theme

Introduction to Theme “Chromatin, Epigenetics, and Transcription”
Joan W. Conaway p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p61
The COMPASS Family of Histone H3K4 Methylases:
Mechanisms of Regulation in Development
and Disease Pathogenesis
Ali Shilatifard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p65
Programming of DNA Methylation Patterns
Howard Cedar and Yehudit Bergman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p97
RNA Polymerase II Elongation Control
Qiang Zhou, Tiandao Li, and David H. Price p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 119
Genome Regulation by Long Noncoding RNAs
John L. Rinn and Howard Y. Chang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 145

Protein Tagging Theme

The Ubiquitin System, an Immense Realm
Alexander Varshavsky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 167
Ubiquitin and Proteasomes in Transcription
Fuqiang Geng, Sabine Wenzel, and William P. Tansey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 177

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The Ubiquitin Code

David Komander and Michael Rape p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 203
Ubiquitin and Membrane Protein Turnover: From Cradle to Grave
Jason A. MacGurn, Pi-Chiang Hsu, and Scott D. Emr p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 231
The N-End Rule Pathway
Takafumi Tasaki, Shashikanth M. Sriram, Kyong Soo Park, and Yong Tae Kwon p p p 261
Ubiquitin-Binding Proteins: Decoders of Ubiquitin-Mediated
Cellular Functions
Koraljka Husnjak and Ivan Dikic p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 291
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Ubiquitin-Like Proteins
Annemarthe G. van der Veen and Hidde L. Ploegh p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 323
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Recent Advances in Biochemistry

Toward the Single-Hour High-Quality Genome
Patrik L. Ståhl and Joakim Lundeberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359
Mass Spectrometry–Based Proteomics and Network Biology
Ariel Bensimon, Albert J.R. Heck, and Ruedi Aebersold p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 379
Membrane Fission: The Biogenesis of Transport Carriers
Felix Campelo and Vivek Malhotra p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 407
Emerging Paradigms for Complex Iron-Sulfur Cofactor Assembly
and Insertion
John W. Peters and Joan B. Broderick p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 429
Structural Perspective of Peptidoglycan Biosynthesis and Assembly
Andrew L. Lovering, Susan S. Safadi, and Natalie C.J. Strynadka p p p p p p p p p p p p p p p p p p p p 451
Discovery, Biosynthesis, and Engineering of Lantipeptides
Patrick J. Knerr and Wilfred A. van der Donk p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 479
Regulation of Glucose Transporter Translocation
in Health and Diabetes
Jonathan S. Bogan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 507
Structure and Regulation of Soluble Guanylate Cyclase
Emily R. Derbyshire and Michael A. Marletta p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 533
The MPS1 Family of Protein Kinases
Xuedong Liu and Mark Winey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 561
The Structural Basis for Control of Eukaryotic Protein Kinases
Jane A. Endicott, Martin E.M. Noble, and Louise N. Johnson p p p p p p p p p p p p p p p p p p p p p p p p p p 587

vi Contents
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Measurements and Implications of the Membrane Dipole Potential

Liguo Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 615
GTPase Networks in Membrane Traffic
Emi Mizuno-Yamasaki, Felix Rivera-Molina, and Peter Novick p p p p p p p p p p p p p p p p p p p p p p p 637
Roles for Actin Assembly in Endocytosis
Olivia L. Mooren, Brian J. Galletta, and John A. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 661
Lipid Droplets and Cellular Lipid Metabolism
Tobias C. Walther and Robert V. Farese Jr. p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 687
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Adipogenesis: From Stem Cell to Adipocyte

Qi Qun Tang and M. Daniel Lane p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 715
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Pluripotency and Nuclear Reprogramming

Marion Dejosez and Thomas P. Zwaka p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 737
Endoplasmic Reticulum Stress and Type 2 Diabetes
Sung Hoon Back and Randal J. Kaufman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 767
Structure Unifies the Viral Universe
Nicola G.A. Abrescia, Dennis H. Bamford, Jonathan M. Grimes,
and David I. Stuart p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 795

Indexes
Cumulative Index of Contributing Authors, Volumes 77–81 p p p p p p p p p p p p p p p p p p p p p p p p p p p 823
Cumulative Index of Chapter Titles, Volumes 77–81 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 827

Errata
An online log of corrections to Annual Review of Biochemistry articles may be found at
http://biochem.annualreviews.org/errata.shtml

Contents vii