First draft of slides (Su Lab meeting)

graphics/presentation/RCT-thesis-table2.2.svg

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presentation.mkdn

@@ -4,10 +4,6 @@
   The Scripps Research Institute
 % October 24, 2019
 
-# Intro
-
-# Biological motivation: Transplant rejection
-
 ## Organ transplants are a life-saving treatment for many
 
 \Large
@@ -48,8 +44,6 @@
 
 . . .
 
-\Large
-
 * Rejection is the major long-term threat to organ allografts
 
 ## Allograft rejection remains a major long-term problem
@@ -73,7 +67,7 @@
 
 * Both diagnosis and treatment present significant challenges
 
-* Immune memory is a major confounder
+* Immune memory is the major contributor to long-term rejection
 
 ## My thesis topics
 
@@ -102,153 +96,241 @@ and memory $\mathsf{CD4}^{+}$ T-cell activation
 
 ![Memory T-cells proliferate and respond more quickly](graphics/presentation/T-cells-SVG.pdf)
 
-## Immune memory is a significant contributor to rejection
+## Memory cells are a problem for immune suppression
 
-![Memory T-cells proliferate and respond more quickly](graphics/presentation/T-cells-SVG.pdf)
+\large
 
-# Figure Storage
+Compared to naïve cells, memory cells:
 
-## Slides
-<!-- ## Slide -->
+\normalsize
 
-<!-- ![Figure](graphics/Intro/eBayes-CROP-RASTER.png) -->
+* respond to a lower antigen concentration
+* respond more strongly at any given antigen concentration
+* require less co-stimulation
+* are somewhat independent of some types of co-stimulation required by
+  naïve cells
+* evolve over time to respond even more strongly to their antigen
 
-<!-- ## Slide -->
+. . .
 
-<!-- ![Figure](graphics/CD4-csaw/IDR/D4659vsD5053_epic-PAGE1-CROP-RASTER.png) -->
+\large
 
-<!-- ## Slide -->
+Result:
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me2-sample-MAplot-bins-CROP.png) -->
+\normalsize
 
-<!-- ## Slide -->
+* Memory cells require progressively higher doses of immune suppresive
+  drugs
+* Dosage cannot be increased indefinitely without compromising the
+  immune system's ability to fight infection
 
-<!-- ![Figure](graphics/Intro/med-pval-hist-colored-CROP.pdf) -->
+## We need a better understanding of immune memory
 
-<!-- ## Slide -->
+* Cell surface markers of naïve and memory $\mathsf{CD4}^{+}$ T-cells
+  are fairly well-characterized
+* But internal mechanisms that allow memory cells to respond
+  differently to the same stimulus (antigen presentation) are not
+  well-understood
+  
+. . .
 
-<!-- ![Figure](graphics/CD4-csaw/RNA-seq/PCA-no-batchsub-CROP.png) -->
+* A reasonable hypothesis is that some of these mechanisms are
+  epigenetic: using histone marks or DNA methylation to regulate the
+  expression of certain genes
+* We can test this hypothesis by measuring gene expression (using
+  RNA-seq) and histone methylation (using ChIP-seq) in naïve and
+  memory T-cells before and after activation
+  
+## Experimental design
 
-<!-- ## Slide -->
+* Separately isolate naïve and memory $\mathsf{CD4}^{+}$ T-cells from
+  4 donors
+* Activate with CD3/CD28 beads
+* Take samples at 4 time points: Day 0 (pre-activation), Day 1 (early
+  activation), Day 5 (peak activation), and Day 14 (post-activation)
+* Do RNA-seq + ChIP-seq for 3 histone marks (H3K4me2, H3K4me3, &
+  H3K27me3) for each sample.
 
-<!-- ![Figure](graphics/CD4-csaw/RNA-seq/PCA-combat-batchsub-CROP.png) -->
+Data generated by Sarah Lamere, published in GEO as
+[GSE73214](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE73214)
 
-<!-- ## Slide -->
+## A few intermediate analysis steps are required
 
-<!-- ![Figure](graphics/CD4-csaw/RNA-seq/weights-vs-covars-nobcv-CROP.png) -->
+![Flowchart of workflow for data analysis](graphics/CD4-csaw/rulegraphs/rulegraph-all.pdf)
 
-<!-- ## Slide -->
+## Histone modifications are observed on consecutive histones
 
-<!-- ![Figure](graphics/CD4-csaw/csaw/CCF-plots-noBL-PAGE2-CROP.pdf) -->
+![Strand cross-correlation plots](graphics/CD4-csaw/csaw/CCF-plots-PAGE2-CROP.pdf)
 
-<!-- ## Slide -->
+## Histone modifications are observed on consecutive histones
 
-<!-- ![Figure](graphics/CD4-csaw/csaw/CCF-plots-PAGE2-CROP.pdf) -->
+![ChIP-seq coverage in IL2 gene[^5]](graphics/presentation/LaMere-thesis-fig3.9-SVG-CROP.pdf){ height=70% }
 
-<!-- ## Slide -->
+[^5]: Sarah LaMere. "Dynamic epigenetic regulation of CD4 T cell activation and memory formation". PhD thesis. TSRI, 2015.
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me2-PCA-raw-CROP.png) -->
+## Finding enriched regions across the genome
 
-<!-- ## Slide -->
+* Scan across the genome looking for regions with read coverage above
+  background level in each donor using SICER peak caller
+* Use Irreducible Discovery Rate framework to identify peaks that are
+  called consistently across multiple donors
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me2-PCA-SVsub-CROP.png) -->
+![Peak-calling summary statistics](graphics/presentation/RCT-thesis-table2.2-SVG-CROP.pdf)
 
-<!-- ## Slide -->
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me3-PCA-raw-CROP.png) -->
+## Each histone mark has an "effective promoter radius"
 
-<!-- ## Slide -->
+![Enrichment of peaks near promoters](graphics/CD4-csaw/Promoter-Peak-Distance-Profile-PAGE1-CROP.pdf)
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me3-PCA-SVsub-CROP.png) -->
+## Peaks in promoters are correlated with gene expression
 
-<!-- ## Slide -->
+<!-- TODO: Pull out one column and rotate it -->
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K27me3-PCA-raw-CROP.png) -->
+![Expression distributions of genes with and without promoter peaks](graphics/CD4-csaw/FPKM-by-Peak-Violin-Plots-CROP.pdf)
 
-<!-- ## Slide -->
+## The story so far
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K27me3-PCA-SVsub-CROP.png) -->
+* H3K4me2, H3K4me3, and H3K27me3 occur on many consecutive histones in
+  broad regions across the genome
+* These enriched regions occur more commonly within a certain radius
+  of gene promoters
+* This "effective promoter radius" is consistent across all samples
+  for a given histone mark, but differs between histone marks
+* Presence or absence of a peak within this radius is correlated with
+  gene expression
+  
+. . .
 
-<!-- ## Slide -->
+Next: Does the position of a histone modification within a gene
+promoter matter to that gene's expression, or is it merely the
+presence or absence anywhere within the promoter?
+  
+## H3K4me2 promoter neighborhood K-means clusters
 
-<!-- ![Figure](graphics/CD4-csaw/MOFA-varExplaiend-matrix-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K4me2-neighborhood-clusters-CROP.png)
 
-<!-- ## Slide -->
+## H3K4me2 promoter neighborhood cluster PCA
 
-<!-- ![Figure](graphics/CD4-csaw/MOFA-LF-scatter-small.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K4me2-neighborhood-PCA-CROP.png)
 
-<!-- ## Slide -->
+## H3K4me2 promoter neighborhood cluster expression
 
-<!-- ![Figure](graphics/CD4-csaw/MOFA-batch-correct-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K4me2-neighborhood-expression-CROP.png)
 
-<!-- ## Slide -->
+## H3K4me3 promoter neighborhood K-means clusters
 
-<!-- ![Figure](graphics/CD4-csaw/RNA-seq/PCA-final-12-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K4me3-neighborhood-clusters-CROP.png)
 
-<!-- ## Slide -->
+## H3K4me3 promoter neighborhood cluster PCA
 
-<!-- ![Figure](graphics/CD4-csaw/Promoter-Peak-Distance-Profile-PAGE1-CROP.pdf) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K4me3-neighborhood-PCA-CROP.png)
 
-<!-- ## Slide -->
+## H3K4me3 promoter neighborhood cluster expression
 
-<!-- ![Figure](graphics/CD4-csaw/FPKM-by-Peak-Violin-Plots-CROP.pdf) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K4me3-neighborhood-expression-CROP.png)
 
-<!-- ## Slide -->
+## H3K27me3 promoter neighborhood K-means clusters
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me2-promoter-PCA-group-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K27me3-neighborhood-clusters-CROP.png)
 
-<!-- ## Slide -->
+## H3K27me3 promoter neighborhood cluster PCA
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me3-promoter-PCA-group-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K27me3-neighborhood-PCA-CROP.png)
 
-<!-- ## Slide -->
+## H3K27me3 promoter neighborhood cluster expression
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K27me3-promoter-PCA-group-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K27me3-neighborhood-expression-CROP.png)
 
-<!-- ## Slide -->
+## What have we learned?
 
-<!-- ![Figure](graphics/CD4-csaw/RNA-seq/PCA-final-23-CROP.png) -->
+### H3K4me2 & H3K4me3
 
-<!-- ## Slide -->
+* Peak closer to promoter $\Rightarrow$ more likely gene is highly
+  expressed
+* Slightly asymmetric in favor of peaks downstream of TSS
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me2-neighborhood-clusters-CROP.png) -->
+. . .
 
-<!-- ## Slide -->
+### H3K27me3
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me2-neighborhood-PCA-CROP.png) -->
+* Depletion of H3K27me3 at TSS associated with elevated gene
+  expression
+* Enrichment of H3K27me3 upstream of TSS even more strongly associated
+  with elevated expression
+* Other coverage profiles not associated with elevated expression
 
-<!-- ## Slide -->
+## Differential modification disappears by Day 14
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me2-neighborhood-expression-CROP.png) -->
+![Differential modification between naïve and memory samples at each time point](graphics/presentation/RCT-thesis-table2.4-SVG-CROP.pdf)
 
-<!-- ## Slide -->
+## Convergence at Day 14 H3K4me2
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me3-neighborhood-clusters-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K4me2-promoter-PCA-group-CROP.png)
 
-<!-- ## Slide -->
+## Convergence at Day 14 H3K4me3
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me3-neighborhood-PCA-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K4me3-promoter-PCA-group-CROP.png)
 
-<!-- ## Slide -->
+## Convergence at Day 14 H3K27me3
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K4me3-neighborhood-expression-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/ChIP-seq/H3K27me3-promoter-PCA-group-CROP.png)
 
-<!-- ## Slide -->
+## Convergence at Day 14 RNA-seq (PC 2 & 3)
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K27me3-neighborhood-clusters-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/RNA-seq/PCA-final-23-CROP.png)
 
-<!-- ## Slide -->
+## MOFA identifies shared variation across all 4 data sets
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K27me3-neighborhood-PCA-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/MOFA-varExplaiend-matrix-CROP.png)
 
-<!-- ## Slide -->
+## MOFA shared variation captures convergence pattern
 
-<!-- ![Figure](graphics/CD4-csaw/ChIP-seq/H3K27me3-neighborhood-expression-CROP.png) -->
+![(Insert figure legend)](graphics/CD4-csaw/MOFA-LF-scatter-small.png)
 
-<!-- ## Slide -->
+## What have we learned?
 
-<!-- ![Figure](graphics/CD4-csaw/LaMere2016_fig8.pdf) -->
+* Almost no differential modification observed between naïve and
+  memory at Day 14, despite plenty of differential modification at
+  earlier time points.
+* RNA-seq data and all 3 histone marks' ChIP-seq data all show
+  "convergence" between naïve and memory by Day 14 in the first 2 or 3
+  principal coordinates.
+* MOFA captures this convergence pattern in one of the latent factors,
+  indicating that this is a shared pattern across all 4 data sets.
 
 <!-- ## Slide -->
 
-<!-- ![Figure](graphics/CD4-csaw/rulegraphs/rulegraph-all.pdf) -->
+<!-- ![(Insert figure legend)](graphics/CD4-csaw/LaMere2016_fig8.pdf) -->
+
+
+## Takeaway 1: Each histone mark has an "effective promoter radius"
+
+* H3K4me2, H3K4me3, and H3K27me3 ChIP-seq reads are enriched in broad
+  regions across the genome, representing areas where the histone
+  modification is present
+* These enriched regions occur more commonly within a certain radius
+  of gene promoters
+* This "effective promoter radius" is specific to each histone mark
+* Presence or absence of a peak within this radius is correlated with
+  gene expression
+  
+## Takeaway 2: Peak position within the promoter is important
+
+* H3K4me2 and H3K4me3 peaks are more strongly associated with elevated
+  gene expression the closer they are to the TSS, with a slight bias
+  toward downstream peaks.
+* H3K27me3 depletion at the TSS and enrichement upstream are both
+  associated with elevated expression, while other patterns are not.
+* In all histone marks, position of modification within promoter
+  appears to be an important factor in association with gene
+  expression
+
+## Takeaway 3: Expression & epigenetic state both converge at Day 14
+
+* At Day 14, almost no differential modification observed between
+  naïve and memory cells
+* Naïve and memory converge visually in PCoA plots
+* Convergence is a shared pattern of variation across all 3 histone
+  marks and gene expression
+* This is consistent with the hypothesis that the naïve cells have
+  differentiated into a more memory-like phenotype by day 14.