ZNF198 Stabilizes the LSD1–CoREST–HDAC1 Complex on
Chromatin through Its MYM-Type Zinc Fingers
Christian B. Gocke, Hongtao Yu*
Howard Hughes Medical Institute, Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
Histone modifications in chromatin regulate gene expression. A transcriptional co-repressor complex containing LSD1–
CoREST–HDAC1 (termed LCH hereafter for simplicity) represses transcription by coordinately removing histone
modifications associated with transcriptional activation. RE1-silencing transcription factor (REST) recruits LCH to the
promoters of neuron-specific genes, thereby silencing their transcription in non-neuronal tissues. ZNF198 is a member of a
family of MYM-type zinc finger proteins that associate with LCH. Here, we show that ZNF198-like proteins are required for
the repression of E-cadherin (a gene known to be repressed by LSD1), but not REST-responsive genes. ZNF198 binds
preferentially to the intact LCH ternary complex, but not its individual subunits. ZNF198- and REST-binding to the LCH
complex are mutually exclusive. ZNF198 associates with chromatin independently of LCH. Furthermore, modification of
HDAC1 by small ubiquitin-like modifier (SUMO) in vitro weakens its interaction with CoREST whereas sumoylation of HDAC1
stimulates its binding to ZNF198. Finally, we mapped the LCH- and HDAC1–SUMO-binding domains of ZNF198 to tandem
repeats of MYM-type zinc fingers. Therefore, our results suggest that ZNF198, through its multiple protein-protein
interaction interfaces, helps to maintain the intact LCH complex on specific, non-REST-responsive promoters and may also
prevent SUMO-dependent dissociation of HDAC1.
Citation: Gocke CB, Yu H (2008) ZNF198 Stabilizes the LSD1–CoREST–HDAC1 Complex on Chromatin through Its MYM-Type Zinc Fingers. PLoS ONE 3(9): e3255.
Editor: Wenqing Xu, University of Washington, United States of America
Received July 8, 2008; Accepted August 25, 2008; Published September 22, 2008
Copyright: ? 2008 Gocke, Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Welch foundation, the WM Keck Foundation, the March of Dimes Foundation, and the Leukemia and Lymphoma
Society. HY is an Investigator at the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
The ordered assembly of genomic DNA into a proteinacious
substance—chromatin—allows for high-order regulation of DNA-
templated processes, such as transcription, replication, and DNA
repair. Chromatin contains repeating units of nucleosomes, which
consists of one histone H3/H4 tetramer and two H2A/H2B
dimers wrapped around by double-stranded DNA [1–3]. Polymers
of nucleosomes flanked by various lengths of linker DNA can fold
into compacted high-order structures that are subject to dynamic
Post-translational modifications on the flexible tails of histones
can directly or indirectly affect chromatin structure . Histone
acetylation is generally associated with transcriptional activation
and is dynamically regulated by histone acetyltransferases (HATs)
and histone deacetylases (HDACs) . The effect of histone lysine
methylation, catalyzed by methyltransferases, depends on the
specific residue and degree of modification (mono-, di-, or
trimethylation) . Histone H3 lysine 4 di- and trimethylation
(H3K4me2/3) is associated with active promoters [7,8], but
H3K9me2/3 is mostly associated with transcriptional repression
. Lysine-specific demethylase 1 (LSD1; also known as BHC110
or AOF2) is a flavin adenine dinucleotide (FAD)-dependent amine
oxidase that demethylates histone H3K4me1/2, but not H3K4me3
[10,11]. Although LSD1 alone can demethylate bulk histones or
peptide substrates, it requires a co-factor, REST co-repressor
(CoREST), for efficient binding to nucleosomes and demethylation
of nucleosomal substrates [12–14]. The LSD1–CoREST interac-
abundant class I HDACs, HDAC1 and HDAC2, associate with
LSD1–CoREST, forming an LSD1–CoREST–HDAC1/2 (LCH)
core ternary complex [15–18]. Formation of this complex on
chromatin enables HDAC1/2 and LSD1 to stimulate each other’s
activity through CoREST .
The LCH complex can be targeted to specific promoters
through binding to sequence-specific transcriptional factors, either
directly or indirectly. For example, RE1-silencing transcription
factor (REST), which is a Kru ¨ppel-like zinc finger-containing
protein, binds directly to CoREST and recruits the LCH complex
to neuron-specific gene promoters that contain RE1 elements, thus
repressing the expression of neuron-specific genes in non-neuronal
tissues [20,21]. In addition, LCH can be incorporated into a larger
co-repressor complex that also contains CtBP1/2 and the G9a
histone H3K9 methyltransferase . CtBP1/2 in turn binds to
Kru ¨ppel-like zinc finger-containing sequence-specific repressors
ZEB1/2, which recruit this complex to chromatin . Finally,
LSD1 is targeted to androgen- and estrogen-responsive promoters
through interactions with androgen receptor (AR) and possibly
estrogen receptor (ER). In this context, LSD1 activates transcrip-
tion through promoting the demethylation of H3K9me1/2 at
these promoters [23,24]. Whether the entire LCH complex is
targeted to AR- or ER-dependent promoters is unclear.
Several human proteins, including ZNF198, ZNF237, ZNF261,
ZNF262, and ZNF258, contain a stretch of unique tandem zinc
PLoS ONE | www.plosone.org1 September 2008 | Volume 3 | Issue 9 | e3255
fingers called MYM (myeloproliferative and mental retardation)
domains  (Figure S1). The MYM-domains of ZNF198 are
frequently fused to FGF receptor kinase in myeloproliferative
syndromes [26–28]. Disruptions near the ZNF261 gene have been
linked to X-linked mental retardation . Among human MYM-
domain proteins, ZNF198, ZNF261, and ZNF262 share a similar
domain architecture and possibly perform similar functions (Figure
S1). A Drosophila homolog of these proteins, without children
(dWoc), is essential for viability, associates with chromatin, and
prevents telomere fusions [30–32]. Interestingly, ZNF198 and
ZNF261 are present in transcriptional corepressor complexes that
also contain LCH [13,14,18], although their functions in
transcriptional regulation have not been explored.
Many transcription factors and cofactors are modified by small
ubiquitin-like modifier (SUMO). Sumoylation of these factors
generally leads to transcriptional repression. For unknown reasons,
multiple subunits within a given chromatin-associated complex are
often targeted by sumoylation [33,34]. For example, ZNF198,
ZNF262, HDAC1, and LSD1 are known SUMO substrates
[33,35–37]. Sumoylation of HDAC1 has been shown to be
required for its function. Recent reports have also identified
ZNF198 as a non-covalent binding partner for SUMO [38,39].
In this study, we characterize the function and mechanism of
ZNF198-like proteins in regulating the LCH complex. We show
that depletion of ZNF198, ZNF261, and ZNF262 by RNA
interference (RNAi) in HeLa cells causes derepression of E-
cadherin, a known target of LSD1. By contrast, ZNF198-like
proteins are not required for the transcriptional repression of
several REST-responsive genes that are repressed by LSD1.
Consistent with this finding, ZNF198 selectively binds to the
LSD1–CoREST–HDAC1 ternary complex and binding of
ZNF198 to LCH prevents its interaction with REST. Similar to
dWoc, ZNF198 associates with chromatin. Depletion of ZNF198-
like proteins weakens the association of LCH with chromatin.
Furthermore, sumoylation of HDAC1 decreases its affinity toward
CoREST, but enhances its binding to ZNF198. Finally, the
tandem repeats of MYM-type zinc fingers of ZNF198 mediate its
binding to both LCH and sumoylated HDAC1. Collectively, our
results suggest that, unlike the Kru ¨ppel-like zinc fingers which bind
to DNA, the MYM-type zinc fingers of ZNF198-like proteins
mediate multiple protein-protein interactions, maintains the
integrity of the LCH complex at non-REST-responsive promoters,
and may antagonize SUMO-dependent disassembly of the LCH
ZNF198 associates with LSD1, CoREST, and HDACs in
The MYM-type zinc fingers have the CX2CX19–24[F/
Y]CX3CX3[F/Y] (X is any residue) consensus motif . Five
proteins in the human proteome contain tandem repeats of the
MYM-type zinc fingers, including ZNF198, ZNF261, ZNF262,
ZNF237, and ZNF258 (Figure S1). Some of the MYM zinc fingers
in ZNF237 and ZNF258 lack key conserved cysteines (Figure S1),
whereas the zinc fingers in ZNF198, ZNF261, and ZNF262 all
appear to be intact. ZNF198, ZNF261, and ZNF262 have
additional features that differentiate them from ZNF237 and
ZNF258. They contain a proline/valine-rich (P/V-rich) domain
downstream of the MYM domain. They also contain a domain at
their C-terminal region that is predicted by 3D-Jury  to have a
fold similar to DNA breaking-rejoining enzymes, such as Cre
recombinase. The Cre-like domain is also found in several proteins
that do not contain MYM zinc fingers (Figure S1).
ZNF198 and ZNF261 have been shown to be present in several
LSD1-containing transcriptional corepressor complexes in sub-
stoichiometric amounts [13,14,18]. To identify the major
ZNF198-interacting proteins in human cells, we immunoprecip-
itated the endogenous ZNF198 protein from HEK293 and HeLa
cells (Figure 1A and data not shown). The ZNF198-binding
proteins were detected by Colloidal blue staining followed by mass
spectrometry. LSD1, CoREST, and HDAC1/2 were present at
near stoichiometric levels. ZNF262 was also present at sub-
stoichiometric amounts. Several abundant proteins, including
tubulin, Hsp70, and dynein, were also identified in the anti-
ZNF198 IP, although they might not be specific ZNF198
interactors. This result indicates that LSD1, CoREST, and
HDAC1/2 are major binding proteins of ZNF198 in human cells
and confirms earlier findings that have demonstrated the
interactions between the LCH complex and proteins containing
MYM zinc fingers.
ZNF198-like proteins are not required for the repression
of REST-responsive genes
Through its binding to REST, the LCH complex is recruited to
neuron-specific genes and represses their transcription in non-
neuronal tissues. We first tested whether ZNF198-like proteins
were required for the repression of REST-responsive genes.
Because ZNF198, ZNF261, and ZNF262 have all been shown to
be associated with LSD1-containing corepressor complexes, we
depleted from U2OS and other human cells the three ZNF198-
like MYM proteins using RNA intereference (RNAi). As shown in
Figure 1B, RNAi against ZNF198, ZNF261, and ZNF262
effectively knocked down the levels of ZNF198 without affecting
the levels of LSD1, CoREST, or HDAC1. We did not have
antibodies against ZNF261 and ZNF262. However, quantitative
RT-PCR analysis (QPCR) confirmed that the siRNAs against
these two genes effectively reduced their mRNA levels (Figure 1C).
As a comparison, we also depleted LSD1 from human cells using
RNAi. Cells transfected with siRNA against luciferase were used
as a control. As expected, QPCR analysis revealed that LSD1
RNAi caused an up-regulation of mRNA levels of the known
LSD1 target genes, SCN3A and NCAM2  (Figure 1D). By
contrast, depletion of ZNF198-like proteins did not significantly
alter the mRNA levels of SCN3A and NCAM2 (Figure 1D),
suggesting that these proteins were not required for the repression
of these putative REST-responsive neuronal genes in non-
To identify additional genes that were repressed by LSD1, we
performed microarray analysis of RNA samples from HeLa cells
transfected with siRNAs against luciferase or LSD1 (data not
shown). Among the genes that were up-regulated by LSD1 RNAi,
we confirmed that keratin 17 (KRT17) was a REST-responsive
gene, because REST directly bound to the promoter of KRT17 as
(Figure 2A). Using QPCR, we confirmed that LSD1 RNAi indeed
increased the mRNA levels of KRT17. Depletion of ZNF198-like
MYM proteins again had no effect on KRT17 expression
(Figure 2B). Therefore, these ZNF198-like proteins do not appear
to be required for the repression of REST-responsive genes.
ZNF198-like proteins are required for the repression of E-
Corepressor complexes containing LSD1, CoREST, and
HDAC1 can be recruited to promoters in REST-independent
ways. E-cadherin is a well-characterized gene that is repressed by
the CtBP corepressor complex containing LSD1, but E-cadherin is
LSD1 Regulation by ZNF198
PLoS ONE | www.plosone.org2 September 2008 | Volume 3 | Issue 9 | e3255
In vitro binding and sumoylation assays
In vitro transcription and translation and in vitro sumoylation
assays were performed as previously described . For binding
assays, HDAC1-FLAG, GST-CoREST, or GST-SUMO1/2
proteins together with other proteins were incubated with 5–
10 ml M2 agarose (Sigma) or glutathione-sepharose 4B (Amer-
sham) beads in 50 ml binding solution (TBS supplemented with
0.05% Tween-20 and 1 mM DTT) for 1 hr. After washing, the
beads were then incubated in 50 ml blocking solution (TBS
supplemented with 0.05% Tween-20, 5% dry milk, 1 mM DTT)
for 1 hr at room temperature. The appropriate recombinant
proteins or 5 ml
incubated with the beads for 1 hr at room temperature. Beads
were then washed four times with the binding solution, boiled in
SDS sample buffer, and subjected to SDS-PAGE followed by
Coomassie Blue staining and autoradiography. For binding
reactions containing ZNF198, 100 mM ZnCl2 was included in
35S-labeled in vitro translated proteins were
Reverse transcription and quantitative PCR
RNAfrom U2OScellsgrownon6-wellplatesand transfectedwith
siRNAs was extracted using TriZOLreagent (Invitrogen) followed by
RNAeasy RNA purification kit (Qiagen). RNA was then subjected to
DNase digestion and inactivation followed by reverse transcription
using random hexamers as primers. 2.5 ml of this cDNA was then
mix (Bio-Rad). The primers used were: SCN3A-Fwd (59-ATGCT-
GGGCTTTGTTATGCT-39), SCN3A-Rev (59-TGGCTTGGC-
TTCAGTTTTCT-3); Cyclophilin B-Fwd: (59-GGAGATGGCA-
CAGGAGGAA-39), Cyclophilin B-Rev (59-GCCCGTAGTGCTT-
CAGTTT-39); E-cadherin-Fwd (59-GGATGACACAGCGTGA-
GAC-39), NCAM2-Fwd (59-CACGTTCACTGAAGGCGATA-
KRT17-Fwd (59-ATGCAGGCCTTGGAGATAGA-39), KRT17-
Rev (59-AGGGATGCTTTCATGCTGAG-39). All primers were
validated as described .
Chromatin immunoprecipitation (ChIP)
ChIP experiments were performed as described . About
16107HeLa Tet-on cells was used for each IP. Quantitative PCR
was performed with 2.5 ml of eluted DNA, using the following
TCTTTTC-39), GAPDH ChIP-Rev (59-TATTGAGGGCAGG-
proteins. The following color schemes from this illustration are
used throughout the manuscript: MYM-type zinc fingers (MYM,
red); proline/valine-rich domain (P/V-rich, green); Cre-like
domain (CLD, gold); glutamine-rich domain (Q-rich, gray);
potassium-tetramerization domain (K-tetra, black); and transpos-
ase-like domain (teal). Non-cysteine residues at zinc-coordinating
positions in certain MYM domains are indicated by asterisks.
Scale bar indicates 100 amino acids. The Cre-like domain of
KCTD1 was used for 3D-Jury analysis (http://Bioinfo.Pl/Meta).
Found at: doi:10.1371/journal.pone.0003255.s001 (0.50 MB TIF)
Domain architecture of MYM domain-containing
HDAC1 or LSD1. (A) 35S-labeled in vitro translated ZNF198
was incubated with sumoylation enzymes (E1 and E2) and ATP in
the presence or absence of SUMO2. The reaction mixtures were
separated by SDS-PAGE and analyzed using a phosphoimager.
The bands of unmodified and sumoylated ZNF198 are labeled. (B)
Mixtures of His-LSD1 (300 ng), HDAC1-FLAG (300 ng), and
GST-CoREST (100 ng) were subjected to in vitro sumoylation
reactions in the presence or absence of His-ZNF198 (1–2 mg). The
reaction mixtures were blotted with anti-FLAG (top panel) or anti-
LSD1 (bottom panel).
Found at: doi:10.1371/journal.pone.0003255.s002 (0.33 MB TIF)
ZNF198 does not stimulate the sumoylation of
We thank Jenny Hsieh for reagents. We also thank Maojun Yang for
assistance with protein purification, Ryan Potts and Jungseog Kang for
helpful discussions, and Nick Grishin for protein structure predictions.
Conceived and designed the experiments: CBG HY. Performed the
experiments: CBG. Analyzed the data: CBG HY. Wrote the paper: CBG
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