Discovering chromatin motifs using FAIRE sequencing and the human diploid genome
- Chia-Chun Yang†1, 2,
- Michael J Buck†3,
- Min-Hsuan Chen2,
- Yun-Fan Chen2,
- Hsin-Chi Lan1,
- Jeremy JW Chen1, 4, 5,
- Chao Cheng6, 7 and
- Chun-Chi Liu2, 4, 5Email author
© Yang et al.; licensee BioMed Central Ltd. 2013
Received: 24 May 2012
Accepted: 30 April 2013
Published: 8 May 2013
Specific chromatin structures are associated with active or inactive gene transcription. The gene regulatory elements are intrinsically dynamic and alternate between inactive and active states through the recruitment of DNA binding proteins, such as chromatin-remodeling proteins.
We developed a unique genome-wide method to discover DNA motifs associated with chromatin accessibility using formaldehyde-assisted isolation of regulatory elements with high-throughput sequencing (FAIRE-seq). We aligned the FAIRE-seq reads to the GM12878 diploid genome and subsequently identified differential chromatin-state regions (DCSRs) using heterozygous SNPs. The DCSR pairs represent the locations of imbalances of chromatin accessibility between alleles and are ideal to reveal chromatin motifs that may directly modulate chromatin accessibility. In this study, we used DNA 6-10mer sequences to interrogate all DCSRs, and subsequently discovered conserved chromatin motifs with significant changes in the occurrence frequency. To investigate their likely roles in biology, we studied the annotated protein associated with each of the top ten chromatin motifs genome-wide, in the intergenic regions and in genes, respectively. As a result, we found that most of these annotated motifs are associated with chromatin remodeling, reflecting their significance in biology.
Our method is the first one using fully phased diploid genome and FAIRE-seq to discover motifs associated with chromatin accessibility. Our results were collected to construct the first chromatin motif database (CMD), providing the potential DNA motifs recognized by chromatin-remodeling proteins and is freely available at http://syslab.nchu.edu.tw/chromatin.
Chromatin is comprised of repeating nucleosome units consisting of ~146 base pairs of DNA coiled around an octamer of four core histone proteins (H2A, H2B, H3 and H4) . The chromatin surrounding the actively transcribed genes is relaxed, and importantly, a nucleosome-depleted region (NDR) is observed immediately upstream the transcriptional start site. The presence of a NDR is characteristic of both CpG-rich  and CpG-poor  promoters where transcription factors (TFs) can approach to facilitate transcription.
Gene regulatory elements are intrinsically dynamic and alternate between inactive and active states through the recruitment of DNA binding proteins, such as chromatin remodelers, that regulate nucleosome stability . The formation of open chromatin, or nucleosome disassembly, and its association with transcriptional activity are an evolutionarily conserved characteristic . To date, FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) , or FAIRE-seq (concerting with massive parallel sequencing), is extensively used to identify cell-specific chromatin states, and to investigate the relationship between chromatin structures and diseases [7–11]. For example, Waki et al. performed computational motif analysis of the adipocyte-specific FAIRE peaks (open chromatin sites) and discovered an enrichment of a binding motif for nuclear family I (NFI) transcription factors . In addition, Song et al. analyzed FAIRE-seq and DNase-seq data in seven cell lines and identified cell-specific regulatory elements . Those studies take advantage of such technology to further reveal the nature of gene regulation. Nevertheless, the effects of allele-specific variations were not considered, and we believe that they may play important roles in chromatin structures.
Recently, Rozowsky et al. integrated RNA-seq, ChIP-seq and the diploid genome sequence to identify allele-specific TF binding sites . Meanwhile, McDaniell et al. integrated DNase-seq, CTCF ChIP-seq and parent–child trios to identify heritable allele-specific chromatin signatures . However, de novo DNA motifs associated with allele-specific chromatin accessibility have not been reported yet. Therefore, we developed the first method for discovering de novo DNA motifs associated with chromatin accessibility using FAIRE-seq and the diploid genome sequence. We mapped the FAIRE-seq reads to the diploid genome and found differential chromatin-state regions (DCSRs) using heterozygous SNPs. The DCSR pairs represent the locations of imbalances of chromatin accessibility between alleles and are ideal to identify motifs that may directly modulate chromatin accessibility .
Results and discussion
Examining all heterozygous SNPs (~2.3 M heterozygous SNPs) across the genome, we selected the locations with a significant difference in chromatin accessibility between the two alleles. The DCSRs were selected with the following conditions: a SNP was taken into consideration when its read depth had a fold change of >2, and its greater read depth was at least 10 by FAIRE-seq reads. Next, a DCSR was defined to be ±20 bases surrounding such SNP, i.e. 41 bases in total. We used 41 base pairs from both paternal and maternal alleles to build a DCSR pair (Figure 1B).
Chromatin motifs in genome-wide, intergenic, genic, and promoter regions (P value < 0.01)
# Annotated motifs
It is noteworthy that a fully phased diploid genome is important to this study because of the adjacent SNP/indel effect as follows: First, if the distance between the adjacent variations is shorter than the read length, it will affect DCSR detection by changing FAIRE read alignment. Second, if the distance between adjacent variations is < 20 bp, it will affect chromatin motif detection by changing motif frequencies between paternal and maternal alleles.
Discovering conserved motifs with significant changes in the occurrence frequency among DCSRs
Most of the DCSRs differ in one base from their pairs, implying the SNP directly affects chromatin accessibility (Figure 1B). When a heterozygous SNP occurs in a binding site of a TF, either a histone modification enzyme (HME) itself or a HME-recruiting protein, it may determine the state of chromatin. Thus, SNPs among the DCSRs are essential since they carry the information related to the chromatin accessibility. We thus defined the binding motifs associated with chromatin accessibility as chromatin motifs.
Using DNA 6-10mer sequences to interrogate all DCSRs, we subsequently discovered conserved chromatin motifs with significant changes in occurrence frequency between accessible and inaccessible DCSRs (Figure 1C). Additional file 1 shows the chromatin motifs with occurrence rates in inaccessible and accessible chromatin groups in genome-wide regions (P values < 0.01 by paired t-test). There are 1,453 motifs, totally, and 561 (38.6%) of them have higher occurrences in accessible regions than in inaccessible regions. To further eliminate the motifs with low occurrences that might be false positives, we selected motifs that have P values < 0.01 and occurrence rates > 1%. It resulted in 245 genome-wide, 166 intergenic, and 156 genic chromatin motifs (Table 1 and Additional file 2). Since promoter regions only have 103 DCSRs, the number of DCSRs is too small to discover significant motifs. Thus, we did not find any chromatin motif with a P value < 0.01 in promoter regions.
Annotating chromatin motifs using TF databases
Top ten chromatin motifs and TF annotation
MAX USF1 USF2 CREB1 TSNAX ZBTB7A TFEB IRF3 MLX
MAX IRF3 ZBTB25
HCFC2 ZNF193 RAB18
HCFC2 ZNF193 RAB18
RXRA CREB1 ZNF313 ZNF655
MAX USF2 RCOR3 RBM9 GLRX2 ZNF606 CBFA2T3 YBX1 HTATIP IRF3 ESRRA
RXRA CREB1 ZNF313 ZNF655
MAX USF2 RCOR3 RBM9 GLRX2 ZNF606 CBFA2T3 YBX1 HTATIP IRF3 ESRRA
MAX USF1 USF2 CREB1 TSNAX ZBTB7A TFEB IRF3 MLX
HCFC2 ZNF193 RAB18
HCFC2 ZNF193 RAB18
MAX SIRT2 ZNF34 RFXANK ZBTB7A SCAND2 TSNAX KHDRBS1 ZNF655 TP73 IRF3 NFATC1
MAX: Myc and Mad compete with each other to form a heterodimer with Max , and the resulting Myc/Max or Mad/Max protein complex binds to the CACGTG motif through its basic helix-loop-helix leucine zipper domains . The Myc/Max heterodimer is a co-activator that recruits multiple histone acetyl transferase to maintain euchromatin status, whereas the Mad/Max a co-repressor that recruits histone deacetylase (HDAC) to repress transcription. Moreover, Lee et al. identified the genomic binding locations of MYC across 11 different human cell lines using ChIP-seq, and the MYC motif in GM12878 is CCACGTG . This finding is consistent with our top motif CACGTG. RXR/RARA: RXR/RARA recruits histone deacetylase and represses transcription . In addition, RXR/RARA functions as a local chromatin modulator . SOX9: Sox9 interacts with chromatin and activates transcription through the regulation of chromatin modification . MEF2A: The interactions between MyoD homodimers and MEF2 proteins may direct HMEs to the chromatin . HCFC2: HCFC1 and HCFC2 are the core components of the MLL1 complex, which is a histone methyltransferase acting as a positive global regulator during gene transcription . USF1/USF2: USF1/USF2 heterodimer recruits HMEs and maintains the chromatin barrier .
To systematically validate our method, we defined non-differential chromatin-state regions (NDCSRs) by the following conditions: the heterozygous SNPs have a read-depth fold change < 1.5 and the greater allele read depth at least 5 by FAIRE-seq reads. We identified a total of 5,047 pairs of NDCSRs in the GM12878 genome, and then we performed the same framework to obtain significant motifs on NDCSR. Additional file 3 shows the top 100 DCSR and NDCSR motifs with TF annotation. To investigate whether the TF annotation has enrichment with chromatin remodeling, we selected three chromatin-specific GO terms as follows: GO:0016585 chromatin remodeling, GO:0016570 histone modification, and GO:0031490 chromatin DNA binding. In Additional file 3, 29% of DCSR motifs have chromatin-specific annotation and only 8% of NDCSR motifs have chromatin-specific annotation (chi-squared test, P value = 0.0001), suggesting the significant enrichment with chromatin-specific annotation.
MYC allele-specific binding associates and DCSR/NDCSR
Allele-specific MYC peaks
Non-allele-specific MYC peaks
The most significant motif, CACGTG
In Table 2, CACGTG is the most significant motif in both genome-wide (P value = 7.6E-8) and intergenic regions (P value = 1.5E-7). Interestingly, Myc/Max, Mad/Max and USF1/USF2 bind to this motif, and these proteins play the following important roles in chromatin remodeling: the USF1/USF2 heterodimer recruits HMEs to the insulator sites to maintain the chromatin barrier . In mouse studies, Myc and Mad compete with each other to be heterodimerized with Max , and the resulting Myc/Max heterodimer or Mad/Max heterodimer binds to the CACGTG motif through its basic helix-loop-helix leucine zipper domains . Myc/Max heterodimer is a co-activator to recruit multiple histone acetyltransferase to maintain euchromatin status, whereas Mad/Max is a co-repressor that recruits histone deacetylase (HDAC) to repress transcription.
We also found that the significant chromatin motifs are not motifs with high occurrence rate. For example, CACGTG has a low occurrence rate of 1.15% in the inaccessible chromatin groups and a low occurrence rate of 0.69% in the accessible chromatin groups (Additional file 2).
Recently, an increasing number of studies have reported that chromatin accessibility is associated with diseases such as Huntington's disease , muscular dystrophy , breast cancer  and pancreatic cancer , reflecting its importance in biology. Our method is the first one to use a diploid genome and FAIRE-seq to discover motifs associated with chromatin accessibility, which leads to the first chromatin motif database (CMD). The CMD provides the potential DNA motifs recognized by chromatin-remodeling proteins.
FAIRE-seq dataset and the diploid genome sequence
FAIRE-seq reads in GM12878 cell line (GSE32883 ) were downloaded from the UCSC genome browser [6, 16] while diploid genome sequences of GM12878 cell from AlleleSeq . The Bowtie tool  was used to map FAIRE-seq reads to the diploid genome without any mismatch. Accessible and inaccessible chromatin regions were identified based on the read depth on the heterozygous SNPs.
Discovering conserved chromatin motifs
To discover chromatin motifs, we used all combinations of DNA sequences from 6mers to 10mers (~1 M motif candidates) to scan 41-base DCSRs. Since the intergenic and genic regions may have different TFs associated with chromatin remodeling, we performed chromatin motif discovery on the following four type regions: genome-wide, intergenic, genic, and promoter regions (Table 1).
To select the conserved chromatin motifs associated with differential chromatin states, we applied two conditions as follows: (1) either accessible or inaccessible occurrence rate among DCSRs > 1%; and (2) P values < 0.01 by paired t-test, suggesting a significant frequency change between differential chromatin states.
RNA-seq data analysis
We downloaded RNA-seq dataset SRP007417  for GM12878 cells from the NCBI Sequence Read Archive . We utilized Bowtie and TopHat [17, 36] to map short reads to human genome, and then Cufflinks  to estimate the isoform expression level with UCSC KnownGene annotation .
Protein annotation for chromatin motifs
To discover the potential TFs for chromatin modeling, we used two TF databases, the transcription factor encyclopedia (TFe)  and the human protein-DNA interactome (hPDI) database [19, 20]. We downloaded the TF binding site (TFBS) sequences from the TFe database. Since long TFBS sequences might contain several binding sites, we eliminated any of the TFBS sequences with length >30 bases. We aligned sequences of chromatin motifs to TFBS sequences using BLAST alignment with an E-value threshold of 10. With the TFe database, we annotated a chromatin motif using the best E-value of alignment and homology > 80% between the chromatin motif and TFBS sequences. The best alignment is between a chromatin motif and a short TFBS sequence, which indicates that the TF may bind to the chromatin motif. In addition, we used consensus logos from hDPI to provide TF annotation with consensus motifs.
The hDPI database used a protein microarray-based strategy to build human protein-DNA interactome . Xie et al. selected 460 binding motifs and subsequently constructed double-strand DNA probes with lengths of 6 to 34 bases, in which a binding motif may associate with several TFs. The hDPI database has experimental protein-DNA interaction data for humans identified by the protein microarray assays . The hDPI database provided 460 distinct binding motifs and 201 consensus logos for TFs . With the consensus logos, we may have more precise TF annotation but many chromatin-remodeling TFs are not included in consensus logos such as MAX and HDAC1. Thus, we used both binding motifs and 201 consensus logos to annotate chromatin motifs. With the binding motifs, we annotated a chromatin motif using the best E-value of alignment and homology > 80% between the chromatin motif and binding motif sequences. To annotate chromatin motifs with the hDPI consensus logos, we submitted the chromatin motifs to the hPDI web server (http://bioinfo.wilmer.jhu.edu/PDI/) to obtain match scores, and then annotated the chromatin motifs using a match score > 5 between chromatin motifs and consensus logos (Figure 1D). To provide the confidence level of annotation of hDPI consensus logos, the match score of each annotation is shown in Additional file 2. In addition, to provide the accurate annotation, we filtered out the TFs with fragments per kilobase of transcript per million mapped reads (FPKM) < 1 using the RNA-seq data (Figure 1E).
Formaldehyde-assisted isolation of regulatory elements
Differential chromatin-state region
Non-differential chromatin-state region
Chromatin motif database
Single nucleotide polymorphism
Transcription factor encyclopedia
human Protein-DNA Interactome
Fragments Per Kilobase of transcript per Million mapped reads.
This work was supported by the National Science Council grants NSC99-2320-B-005-008-MY3 and NSC101-2627-B-005-002 as well as the Ministry of Education, Taiwan, R.O.C. under the ATU plan.
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