Epigenetic marks and the human transcript diversity

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# Epigenetic marks and the human transcript diversity

![:img_scale 40%](img/GenPhySE-INRA.png)
### GenEpi@Genphyse
#### Guillaume Devailly - 2018/05/14

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# Introduction

- Abundant epigenomic data for model organisms.
- Under-utilised?
- Epigenomic data will soon be abundant for agricultural species too.

## Dataset: ![](img/RoadmapEpigenomics.png)
- RNA-seq
- DNAse1
- WGBS,  10 different histone methylations, 17 different histone acetylations
- 33 cell lines & tissues

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# Objectives

.pull-left[
- Systemic correlation of marks and **gene** transcription level:
  - at TSS
  - at TTS
- Systemic correlation of marks and **exon**:
  - transcription level
  - inclusion ratio
- For **all** genes/exons in **each** cell type.
- For **each** gene/exon in **all** cell types.

]
.pull-right[
![:img_scale 80%](img/H3K4me3_TSS_gene_FPKM_E066_all.png)
]

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# Methodology

**Processed data** taken from RoadmapEpigenomics:
- gene and exon FPKM
- CpG methylation ratios
- DNAse-seq and ChIP-seq coverage

**Reprocessing** of fastq for exon inclusion ratio (aka %spliced, or PSI):
- pseudo-mapping and quantification with [Salmon](https://combine-lab.github.io/salmon/)
- exon Psi for exon **e** of gene **g** using *tpm* quantification of transcripts **t**:
`$$PSI_{ij} = \frac{\sum_{t\subset e} tpm_t}{\sum_{t\in g} tpm_t}$$`

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# What is a gene?
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![:img_scale 100%](img/gencode22.png)
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![:img_scale 53%](img/gene_types.png)
]

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# Where is BRCA1's Transcription Start Site (TSS)?
![:img_scale 68%](img/Human_BRCA1_anno2.png)

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# DNA methylation: ratio *and* density

![:img_scale 100%](img/dname_ex1.png)

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# DNA methylation: ratio *and* density

![:img_scale 100%](img/dname_ex2.png)

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# Promoter DNA methylaton

Lung, all genes

![:img_scale 64%](img/wgbs_TSS_gene_FPKM_E096_all.png)

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# Promoter DNA methylaton

Lung, protein coding genes

![:img_scale 64%](img/wgbs_TSS_gene_FPKM_E096_protein_coding.png)

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# Promoter DNA methylaton

.pull-left[
Lung, lincRNA genes

![:img_scale 100%](img/wgbs_TSS_gene_FPKM_E096_lincRNA.png)
]

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Lung, processed pseudogenes

![:img_scale 100%](img/wgbs_TSS_gene_FPKM_E096_processed_pseudogene.png)
]

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# Activating marks

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DNAse-seq, all genes, H1-derived mesoderm

![:img_scale 85%](img/dnase1_TSS_gene_FPKM_E004_all.png)
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H3K9ac ChIP-seq, all genes, H1-derived mesoderm

![:img_scale 85%](img/H3K9ac_TSS_gene_FPKM_E004_all.png)
]

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# Repressing marks

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H3K27me3, all genes, Thymus

![:img_scale 85%](img/H3K27me3_TSS_gene_FPKM_E112_all.png)
]

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H3K27me3, protein coding genes, Thymus

![:img_scale 85%](img/H3K27me3_TSS_gene_FPKM_E112_protein_coding.png)
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# Assymetric marks

H3K79me2, protein coding genes, H1-derived mesoderm

![:img_scale 41%](img/H3K79me2_TSS_gene_FPKM_E004_protein_coding.png)

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# Exonic marks

H3K36me3, fetal large intestine

![:img_scale 45%](img/H3K36me3.png)

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# Cell by cell *vs* gene by gene

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WGBS, adult liver
![](img/wgbs_TSS_gene_FPKM_E066_all.png)
]

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]

---
class: font180

# Repressing and activating marks

.pull-left[
### mCpG ratio
![:img_scale 80%](img/all_genes_wgbs.png)
]

.pull-right[
### H3K4me3
![:img_scale 80%](img/all_genes_h3k4.png)
]

---

# Summary of results

.pull-left[
<table class="table table-striped" style="font-size: 14px; width: auto !important; margin-left: auto; margin-right: auto;">
 <thead>
 <tr>
 <th style="text-align:left;"> mark </th>
 <th style="text-align:left;"> cell type by cell type </th>
 <th style="text-align:left;"> gene by gene </th>
 <th style="text-align:left;"> center on TSS </th>
 </tr>
 </thead>
<tbody>
 <tr>
 <td style="text-align:left;"> WGBS </td>
 <td style="text-align:left;"> negative </td>
 <td style="text-align:left;"> negative </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> DNAse </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H2A.Z </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> balanced </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K4me1 </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K4me2 </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K4me3 </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K9me3 </td>
 <td style="text-align:left;"> unclear </td>
 <td style="text-align:left;"> unclear </td>
 <td style="text-align:left;"> no </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K23me2 </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> NA </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K27me3 </td>
 <td style="text-align:left;"> negative – variable </td>
 <td style="text-align:left;"> negative </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K36me3 </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> no </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K79me1 </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> no </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K79me2 </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> balanced </td>
 <td style="text-align:left;"> no </td>
 </tr>
</tbody>
</table>
]

.pull-right[
<table class="table table-striped" style="font-size: 14px; width: auto !important; margin-left: auto; margin-right: auto;">
 <thead>
 <tr>
 <th style="text-align:left;"> mark </th>
 <th style="text-align:left;"> cell type by cell type </th>
 <th style="text-align:left;"> gene by gene </th>
 <th style="text-align:left;"> center on TSS </th>
 </tr>
 </thead>
<tbody>
 <tr>
 <td style="text-align:left;"> H2AK5ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H2BK120ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H2BK12ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H2BK15ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> balanced </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H2BK20ac </td>
 <td style="text-align:left;"> neutral </td>
 <td style="text-align:left;"> NA </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H2BK5ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K4ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K9ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K14ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K18ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K23ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K27ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H3K56ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> NA </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H4K8ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H4K12ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> NA </td>
 <td style="text-align:left;"> </td>
 </tr>
 <tr>
 <td style="text-align:left;"> H4K91ac </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> positive </td>
 <td style="text-align:left;"> </td>
 </tr>
</tbody>
</table>

]

---
class: font180

# Lots of results

Combinatorial explosion: > 9000 plots!

.center[
![:img_scale 75%](img/explosion.png)
]

---
class: font160

# PEREpigenomics

*P*rofile *E*xplorer of *R*oadmap *Epigenomic* data  
[www.perepigenomics.roslin.ed.ac.uk](http://www.perepigenomics.roslin.ed.ac.uk/)

.center[
![:img_scale 50%](img/perepigenomics.png)
]

---
class: font180

# Perspective

- Finish PSI analysis.
- Refine features (short *vs* long genes, mono-, bi-, tri- exonic genes, gene families, etc.).
- Other marks.
- Causality analysis using perturbation experiments.
- FAANG data.

---
class: font180

# Thanks

.pull-left[
Anagha Joshi

Anna Mantsoki

Deepti Vipin
]

.pull-right[
![:img_scale 35%](img/logo.png)
![:img_scale 55%](img/GenPhySE-INRA.png)
]