denise sheer inaugural lecture

De Generatione Animalium On the Generation of Animals William Harvey, 1651

Ex ovo omnia From the egg, everything

1578-1657

Denise Sheer ~ Inaugural Lecture 10th May 2010

From the chromosome… everything

Denise Sheer

Centre for Neuroscience & Trauma


Walther Flemming 1843-1905

Antonie van Leeuwenhoek 1632-1723

Polytene chromosomes in Chironomus

Dividing cells Chick red blood cells


Cells behave as they do because of their genes

Cell nucleus

46 chromosomes

Genes DNA


Where do genes map onto chromosomes?

What is the architecture of the chromosome?

Which genetic abnormalities are involved in cancer?


A path travelled well….


Dr Jenni Tsafrir Genetics of eye colour

What was known then about chromosomes? 1965 - Barbara McClintock, Cornell University-Aspects of Gene Control in Higher Organisms

“mechanisms related to.. .the chromosomes…and the highly organized nuclei”.

Down Syndrome


1969-1973 University of the Witwatersrand Johannesburg B.Sc - Zoology & Embryology BSc (Hons) - Zoology

Prof Barry Fabian Prof Boris Balinsky Professor Barry Fabian

nature Lifetime Mentoring Award 2007


Hamburger & Hamilton 1951

Balinsky 1925

Amabis & Cabral 1970


1974-1975 South African Institute of Medical Research

Anti-Snake Venom Primate Research

Prof Trefor Jenkins

Diagnostic genetics

Genetic counselling

Chromosome banding

“Effects of dagga on primate chromosomes”

Down Syndrome


Supervisor: Dr Martin Bobrow

1976-1980 University of Oxford D.Phil.

Sir Walter Bodmer

Reproduced with kind permission of Juliet Wood

X X

x X

X x v

v v v v v v v v v v v v

v v v v v v v

v v v

X

v v v v v v v

v v v v

v v v v v v v

v v v

x

Human Cells

Mouse Cells

Gene 1 Gene 2 Gene 3

Human-Mouse Hybrid Cells

Mapping genes onto chromosomes


Imperial Cancer Research Fund/ Cancer Research UK 1980-1982 Post-Doctoral Research Fellow with Dr. Ellen Solomon 1982-2006 Head: Human Cytogenetics Laboratory




LIMK1

TP53

XPG

ERBA2

ERBA1

APC

MHC

KIR/ILT

TOP2B

FRAX

EIF-5A

NOS1 ELK3

NOS3

HOXB


Mapping the APC gene on chromosome 5

Adenomatous Polyposis Coli APC gene at 5q21

Bodmer et al 1987


Genetic abnormalities in cancer

At the cellular level, cancer is a genetic disease


Acute Lymphoblastic Leukaemia Acute Myelomonocytic Leukaemia

Acute Promyelocytic Leukaemia

Breast Carcinoma

Chronic Myeloid Leukaemia

Colorectal Adenoma

Congenital Fibrosarcoma

Ewing’s Sarcoma

Glioblastoma Krukenberg Tumour

Neuroblastoma

Ovarian Carcinoma

Pancreatic Carcinoma

Primitive Neuro-ectodermal Tumour

Genetic abnormalities in cancer

Ovarian Carcinoma

Glioblastoma

Neuroblastoma

Breast Carcinoma


15;17 identified in all cases of APL Mapping the breakpoints

15;17 chromosome translocation in Acute Promyelocytic Leukaemia

X X

x X

X x

v

V v v v v v v v v v v v

v

Human Cells

Mouse Cells

v v v v v v v

v v V Gene 1

v v v v v v v

v v v

x

Gene 2

Sheer et al 1983

Sheer et al 1985


What is the architecture of the chromosome?

“The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact” Thomas Henry Huxley (1870)

Thomas & Marion Cremer

Comings 1968 Cremer et al 1976

Chinese Hamster cells after focal laser UV irradiation

Chromosome Territories Inter-Chromosome Domain

Cremer et al 1993


Chromosomes occupy discrete territories

Cremer & Cremer 2006 Bolzer et al 2005


6!

TAP2

PS

MB

8 TA

P1

PSM

B9

C2

BF

C4

HLA

-F

HLA

-G

HLA

-A

HLA

-E

HLA

-C

HLA

-B

MIC

B

C6o

rf10

H

LA-D

RA

HLA

-DQ

A1,

2

HLA

-DQ

B1,

2 H

LA-D

OB

HLA

-DM

A H

LA-D

OA

HLA

-DPA

1

RIN

G1

HLA

-DPB

1

TAPB

P

TNF

HSP

A1

TNXB

NO

TCH

4

HLA

-DR

B1,

3,4,

5

* * * *

*

* * *

* *

* * * * * *

* * * *

*

The Major Histocompatibility Complex - a perfect model

MHC-

Cell-Type Specific & Inducible Gene Activity


MHC

Chr 6

Inac&ve Ac&ve

Chromosome architecture is related to gene activity

Volpi et al 2000

Inac&ve Ac&ve

* *

* *

*

*

Ac&ve


2006 Centre for Neuroscience & Trauma Blizard Institute of Cell & Molecular Science Barts & the London School of Medicine & Dentistry Queen Mary University of London

What is the architecture of the chromosome? What are the molecular determinants?

Which genetic abnormalities are involved in cancer? How do children’s brain tumours arise?


Chromosome architecture is dependent on signalling pathways

Inac&ve

Ac&ve

Interferon Gamma

JAK-STAT SIGNALLING

Christova et al 2007 Denise Sheer ~ Inaugural Lecture 10th May 2010

Chromosome architecture is related to gene activity

Inac&ve

Ac&ve

Anchored sites

Ottaviani et al 2008a,b


Genetic abnormalities in paediatric low grade astrocytoma

SEER Denise Sheer ~ Inaugural Lecture 10th May 2010

Tiny duplication on chromosome 7 in pilocytic astrocytoma


Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010

Tiny duplication on chromosome 7 in pilocytic astrocytoma


KIAA1549 BRAF

Genes duplicated on chromosome 7

Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010 Denise Sheer ~ Inaugural Lecture 10th May 2010

KIAA1549 BRAF

KIAA1549 BRAF KIAA1549- BRAF fusion


Genes duplicated on chromosome 7


The MAP kinase signalling pathway

BRAF

MEK1/2

ERK1/2

RAS NF1

Signals from outside the cell


Regulated Cell Division


BRAF

MEK1/2

ERK1/2

RAS

P

P

Regulated Cell Division

NF1


The MAP kinase signalling pathway


BRAF fusion causes cells to keep dividing

MEK1/2

ERK1/2

RAS

P

P

NF1


BRAF KIAA1549

Increased Cell Division


MEK1/2

ERK1/2

RAS

P

P

NF1


BRAF KIAA1549

New opportunities for treatment for pilocytic astrocytoma

Inhibitor

Increased Cell Division


BRAF fusions: A microhomology mediated mechanism?

microhomology

insertion

microhomology

microhomology

microhomology

microhomology

insertion

Lawson, Hindley et al Denise Sheer ~ Inaugural Lecture 10th May 2010

BRAF fusions: A microhomology mediated mechanism?


Where to now?

Where do genes map onto chromosomes? What is the architecture of the chromosome?

Which genetic abnormalities are involved in cancer?

Cremer et al 2006


Centre for Neuroscience and Trauma Prof John Priestley ~ Prof Gavin Giovannoni

Surinder Pal ~ Carol Brown

Sir Nick Wright Prof Tom MacDonald

Prof Mike Curtis Jo Kirner ~ Kerry Newbury

Josie Dance

BLIZARD INSTITUTE OF CELL AND MOLECULAR SCIENCE


Johan Aarum Pavel Bezecny Rossi Christova

Tim Forshew Guy Hindley

Gabriel Jamie Tania Jones

Andrew Lawson Elliott Lever

William Ogunkolade Diego Ottaviani

Chris Pieri Jarek Szary

Ruth Tatevossian Denise Sheer ~ Inaugural Lecture 10th May 2010

Jane Babbage Srinjan Basu Andi Bolzer

Guiseppe Calabrese Edith Chevret Rossen Donev Ceri Edwards

Luda Federova Rachel Gillingham

Pat Gorman Vikki Groves

Peter Johonnett Fiona Kiely

Xin Mao Chiara Mazzanti Paul Mulholland Rosella Muresu Alistair Newall

Rodger Palmer Ketan Patel

Chrys Poulikas Sue Rider

Rebecca Roylance Gabi Senger Carol Shiels

Janet Shipley Petros Takousis

Badmavady Segarane Clare Taylor

Radost Vatcheva Emanuela Volpi Jayson Wang

Sarah Williams Jill Williamson

Pei Jun Wu

Stephan Beck Walter Bodmer Marion Cremer

Thomas Cremer Thomas Down David Ellison

Thomas Jacques Chris Jones Gavin Kelly

David Kelsell Steve Krawetz

Mike Levin Andrew Lister

Antony Michalski Richard Mitter

Paul Mulholland

Dean Nizetic Andrew Pearson

Jon Pritchard Jiannis Ragoussis

Peter Sasieni Janet Shipley Andrew Silver Jeremy Squire

John Trowsdale Frank Uhlmann

Bryan Young


denise sheer inaugural lecture

Health & Medicine