Marc A. Marti-Renom Genome Biology Group (CNAG) Structural Genomics - - PowerPoint PPT Presentation

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Marc A. Marti-Renom Genome Biology Group (CNAG) Structural Genomics - - PowerPoint PPT Presentation

May 25, 2023 38 likes •261 views

Determining the 3D structure of genomes and genomic domains. Marc A. Marti-Renom Genome Biology Group (CNAG) Structural Genomics Group (CRG) Whale sperm myoglobin structure (1960) STRUCTURE FUNCTION alpha-globin genomic domain structure

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SLIDE 1

Determining the 3D structure of genomes and genomic domains.

  • Marc A. Marti-Renom

Genome Biology Group (CNAG) Structural Genomics Group (CRG)

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SLIDE 2

Whale sperm myoglobin structure (1960)

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SLIDE 3

STRUCTURE FUNCTION

alpha-globin genomic domain structure (2011) human genome (2011)

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SLIDE 4
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SLIDE 5

Resolution Gap

Marti-Renom, M. A. & Mirny, L. A. PLoS Comput Biol 7, e1002125 (2011)

μ 10 10 10 Resolution s Time 10 10 10 10 10 10 10 10 μm Volume 10 10 10 10 10 DNA length nt 10 10 10 10

Knowledge

IDM INM

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SLIDE 6

Experiments Computation

Hybrid Method

Baù, D. & Marti-Renom, M. A. Methods 58, 300–306 (2012).

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SLIDE 7

Hi-C technology

Lieberman-Aiden, E. et al. Science 326, 289–293 (2009).

http://3dg.umassmed.edu

A B C D

Chr.18 (Hind III)

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SLIDE 8

Biomolecular structure determination 2D-NOESY data Chromosome structure determination 3C-based data

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SLIDE 9 P1 P2 P1 P2 P1 P2

i i+2 i+1 i+n

Normalization TAD identification 3D Modeling Extract structural properties

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SLIDE 10

On TADs and hormones

Davide Baù François Serra François le Dily

Miguel Beato & Guillaume Filion

Gene Regulation, Stem Cells and Cancer Centre de Regulació Genòmica Barcelona, Spain

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SLIDE 11

Progesterone-regulated transcription in breast cancer

> ¡2,000 ¡genes ¡Up-­‑regulated ¡ > ¡2,000 ¡genes ¡Down-­‑regulated ¡

Regulation in 3D?

Vicent)et#al#2011,))Wright)et#al#2012,)Ballare)et#al#2012)

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SLIDE 12

Experimental design

HiC libraries Chr.18 (NcoI) Chr.18 (Hind III) ChIP-Seq RNA-Seq Hi-C

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SLIDE 13

Are there TADs? how robust?

Chr.18

>30 25 15 10 >30 25 15 10

+Pg

  • Pg

conserved ± 2 0 0 k b o r m o r e 1 0 0 k b

8% 12% 80%

>2,000 detected TADs

Mb) C. Size (M

Chromosome

1 3 5 7 X 9 11 15 13 17 19 21

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SLIDE 14

Are TADs homogeneous?

H3K36me2 H3K4me3 H3K4me1 H3K14ac H3K9me3 H3K27me3 HP1 H1.2

Chr.2

5 Mb

  • Pg
  • 1.0
  • 0.5

0.0 0.5 1.0

Correlation coefficient Same TAD Same random TAD Inter-TADs Consecutive TADs

*** *** ***

Chr.2

5 Mb

+Pg/-Pg

  • 1.0
  • 0.5

0.0 0.5 1.0

Correlation coefficient Same TAD Same random TAD Inter-TADs Consecutive TADs

*** *** ***

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SLIDE 15

Do TADs respond differently to Pg treatment?

Observed/expected ratio (Log2) Frequencies Expression levels (Log2 RPKM) 30 20 10

  • 1
  • 2

2.0 1.5 1.0 0.5 0.0

  • 0.5
  • 1.0

4 3 2 1

  • 1
  • 2
  • 3

Log2 fold change ZBTB2 RMND1 C6orf211 CCDC170 ESR1 SYNE1

  • Pg

+Pg

Expression levels (Log2 RPKM) 4 3 2 1 8 7 6 5 4 3 2 1

  • 1
  • 2

Log2 fold change MRFAP1 S100P MRFAP1L1 BLOC1S4 KIAA0232 TBC1D14 CCDC96 TADA2B GRPEL1

  • Pg

+Pg

Observed Expected 100-90 100-90 0-10 0-10% % of genes per TAD with positive or negative fold change

TAD 469 TAD 821

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SLIDE 16

Do TADs respond differently to Pg treatment?

Observed/expected ratio (Log2) Frequencies Expression levels (Log2 RPKM) 30 20 10
  • 1
  • 2
2.0 1.5 1.0 0.5 0.0
  • 0.5
  • 1.0
4 3 2 1
  • 1
  • 2
  • 3
Log2 fold change ZBTB2 RMND1 C6orf211 CCDC170 ESR1 SYNE1
  • Pg
+Pg Expression levels (Log2 RPKM) 4 3 2 1 8 7 6 5 4 3 2 1
  • 1
  • 2
Log2 fold change MRFAP1 S100P MRFAP1L1 BLOC1S4 KIAA0232 TBC1D14 CCDC96 TADA2B GRPEL1
  • Pg
+Pg Observed Expected 100-90 100-90 0-10 0-10% % of genes per TAD with positive or negative fold change

Repressed TADs Activated TADs Other TADs Mean Replicate 1 Replicate 2 Pg induced fold change per TAD (6h)

Fold change 6h Pg

  • 1.0
  • 0.5

0.0 0.5 1.0 1.5 Fold change per TAD (Log2)

*** *** ***

Fold change 1h Pg

Repressed TADs Activated TADs Other TADs Repressed TADs Activated TADs Other TADs

*** *** ***

  • 2.0
  • 1.0

0.0 1.0 2.0 3.0 Pg induced fold change (log2) per gene

Repressed TADs Activated TADs Other TADs

*** *** ***

Repressed TADs Activated TADs Other TADs

  • 2.0
  • 1.0

0.0 1.0 2.0 Pg induced fold change (log2) per TAD non-coding

  • 3.00
  • 2.00
  • 1.00

0.00 1.00 2.00 3.00

Pg induced changes in intra-TAD interactions (Z-score)

Activated TADs Other TADs Repressed TADs

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SLIDE 17

Chr1:26,800,000-28,700,000

4 3 2

5 4 3 2 1

2.2 0.6 0.9

pool 1 pool 2

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

models (micra) FISH (micra) r= 0.94

1-5 2-4 2-3 3-4

Modeling 3D TADs

61 genomic regions containing 209 TADs covering 267Mb

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SLIDE 18

How TADs respond structurally to Pg?

Repressed TADs Activated TADs Other TADs *** ** 0.8 0.9 1.0 1.1 1.2

PG induced changes in accessibility

Repressed TADs Activated TADs Other TADs *** ** .95 1.00 1.05 1.10

Pg induced changes in radius or giration

non-TSS TSS 20 40 60 80 100

Particle accessibility (%)

***

50 100 150 200 cl12 [13] Pg cl14 [10] mixt cl17 [10] Pg cl11 [30] Pg cl2 [267] Pg cl13 [11] Pg cl1 [297] Pg cl10 [69] Pg cl9 [84] Pg cl16 [10] Pg + cl4 [172] Pg + cl6 [142] Pg + cl7 [89] Pg + cl3 [176] Pg + cl8 [85] Pg + cl15 [10] Pg + cl5 [144] Pg +

dRMSD (nm)

Chr2:9,600,000-13,200,000 Chr2 U170 (activated)

50 100 150 200 cl23 [11] Pg + cl24 [10] Pg + cl5 [34] Pg + cl26 [10] Pg + cl27 [10] Pg + cl28 [10] Pg + cl21 [12] Pg + cl9 [21] Pg + cl19 [14] Pg cl16 [15] Pg cl10 [20] Pg cl6 [32] Pg cl7 [32] Pg cl18 [15] Pg cl25 [10] Pg cl17 [15] Pg cl20 [12] Pg cl3 [73] Pg cl14 [16] Pg cl22 [12] Pg cl13 [16] Pg cl1 [118] Pg cl12 [17] Pg cl4 [46] Pg cl11 [18] Pg cl15 [16] Pg cl2 [112] Pg cl8 [25] Pg

dRMSD (nm)

Chr6:71,800,000-76,500,000 Chr6 U767 (repressed)

  • Pg

+Pg

  • Pg

+Pg

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SLIDE 19

Model for TAD regulation

Structural transition

+ P g

DHS HP1 H1.2 H2A MNAse H3K27me3 H3K9m3 H3K14ac H3K4me1 H3K36me2 H3K4me3

Histone H1 Nucleosome Histones H2A/H2B Progesteone Receptor

Repressed TAD chr1 U41

DHS HP1 H1.2 H2A MNAse H3K27me3 H3K9m3 H3K14ac H3K4me1 H3K36me2 H3K4me3

Activated TAD chr2 U207

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SLIDE 20

STRUCTURE FUNCTION

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SLIDE 21

Structure >> Function!

promoter new enhancer

ESR1

+Pg represses ESR1 gene

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SLIDE 22

Acknowledgments

http://marciuslab.org http://3DGenomes.org http://cnag.cat · http://crg.cat

Davide Baù François le Dily François Serra

  • David Dufour

Mike Goodstadt Gireesh Bogu Francisco Martínez-Jiménez Job Dekker

Program in Systems Biology Department of Biochemistry and Molecular Pharmacology University of Massachusetts Medical School Worcester, MA, USA

Kerstin Bystricky

Chromatin and gene expression Laboratoire de Biologie Moléculaire Eucaryote - CNRS Toulouse, France

Miguel Beato & Guillaume Filion

Gene Regulation, Stem Cells and Cancer Centre de Regulació Genòmica Barcelona, Spain