1

1M

CB

140

11/

29/0

6

The

gene

tics

of h

eter

ochr

omat

in

in m

etaz

oa

3M

CB

140

11/

29/0

64

MC

B 1

40 1

1/29

/06

Her

man

n Jo

seph

Mul

ler

1946

Nob

el P

rize

in M

edic

ine:

"for t

he d

isco

very

of t

he p

rodu

ctio

n of

m

utat

ions

by

mea

ns o

f X-r

ay ir

radi

atio

n"

2

5M

CB

140

11/

29/0

6

Whi

te w

ild-ty

pe

Whi

tem

utan

t

The

true

mea

ning

of "

red

eye

redu

ctio

n":

6M

CB

140

11/

29/0

612

.14

7M

CB

140

11/

29/0

612

.14

8M

CB

140

11/

29/0

6

Gen

e be

havi

or c

an c

hang

e de

pend

ing

on

whe

re o

n th

e ch

rom

osom

e th

e ge

ne li

es.

= “p

ositi

on e

ffect

”(ba

ris

the

mos

t com

mon

ly u

sed

exam

ple)

“Pos

ition

effe

ct v

arie

gatio

n”(P

EV

): ce

ll-to

-cel

l va

riabi

lity

of e

xpre

ssio

n of

a g

ene

that

has

bee

n re

loca

ted

to a

new

pos

ition

in th

e ge

nom

e.

Epi

gene

tic p

heno

men

on:

Sta

ble

chan

ge in

exp

ress

ion

with

out c

hang

e in

seq

uenc

e!

3

9M

CB

140

11/

29/0

6

Enh

ance

r of P

EV

Sup

pres

sor o

f PE

V

10M

CB

140

11/

29/0

6

2 ge

nes:

Su(

var)

2-5

Su(

var)

3-9

11M

CB

140

11/

29/0

612

MC

B 1

40 1

1/29

/06

4

13M

CB

140

11/

29/0

6

HP

1(S

arah

Elg

in)

(het

eroc

hrom

atin

pro

tein

1)

Iden

tifie

d in

a B

IOC

HE

MIC

AL

sche

me

to d

isco

ver p

rote

ins

that

are

ass

ocia

ted

with

he

tero

chro

mat

in.

14M

CB

140

11/

29/0

6

15M

CB

140

11/

29/0

6

HP

1 =

Su(

var)2

-5

Con

serv

ed in

hum

ans

and

in m

ice

(bot

h in

term

s of

seq

uenc

e an

d in

tranu

clea

rlo

catio

n!).

bioc

hem

istry

gene

tics

Why

doe

s H

P1

go to

pla

ces

that

HP

1 go

es to

?

16M

CB

140

11/

29/0

6

“Bio

chem

ical

epi

stas

is”

(T. J

enuw

ein)

Ove

rexp

ress

ion

of m

ouse

Su(

var)

3-9

lead

s to

a

MA

SS

IVE

redi

strib

utio

n of

HP

1 in

the

nucl

eus

of m

ouse

cel

ls.

5

17M

CB

140

11/

29/0

6

Who

wou

ld h

ave

thun

k it?

NC

BI:

Su(

var)

3-9

cont

ains

a d

omai

n (th

e S

ET

dom

ain)

that

is s

omew

hat s

imila

r to,

ah

em, R

UB

ISC

O m

ethy

ltran

sfer

ase.

Su(

var)3

-9 is

a H

ISTO

NE

met

hyltr

ansf

eras

e.

18M

CB

140

11/

29/0

6

His

tone

met

hyla

tion

19M

CB

140

11/

29/0

6

Cal

ling

Dav

id D

ucho

vny

and

Gill

ian

And

erso

n

•S

u(va

r)3-9

was

giv

en th

is n

ame

beca

use

it w

as th

e 9t

hge

ne is

olat

ed o

n th

e 3r

d

chro

mos

ome

in a

scr

een

for S

u(va

r)s.

•It

met

hyla

tes

lysi

ne 9

in h

isto

ne H

3.

This

was

dis

cove

red

18 y

ears

afte

r it w

as

nam

ed.

20M

CB

140

11/

29/0

6

And

fina

lly

•H

P1

pref

eren

tially

BIN

DS

his

tone

H3

met

hyla

ted

on ly

sine

9.

•Th

at’s

why

Su(

var)3

-9 d

eter

min

es

loca

lizat

ion

of H

P1

to h

eter

ochr

omat

in (i

t m

ethy

late

s hi

ston

es in

het

eroc

hrom

atin

).•

At l

east

in fi

ssio

n ye

ast,

and

perh

aps

in

wor

ms,

this

has

to d

o w

ith R

NA

i. ☺

6

21M

CB

140

11/

29/0

622

MC

B 1

40 1

1/29

/06

23M

CB

140

11/

29/0

6

HP1

HP1

24M

CB

140

11/

29/0

6

HP1

HP1HP1

HP1

HP1

HP1

HP1

HP1

==

=

7

25M

CB

140

11/

29/0

6

Rem

embr

ance

of t

hing

s pa

st:

chro

mat

in a

s an

epi

gene

tic v

ehic

le

26M

CB

140

11/

29/0

6

Hom

olog

y(o

rthol

ogs

of h

eter

ocho

mat

in p

rote

ins

in fi

ssio

n ye

ast,

inse

cts,

and

hum

ans)

27M

CB

140

11/

29/0

6

Ana

logy

Fiss

ion

yeas

t, fli

es, m

amm

als.

Bud

ding

yea

st.

28M

CB

140

11/

29/0

6

Nat

ure,

Oct

ober

10,

200

2

The

poly

com

bgr

oup

prot

ein

EZH

2is

invo

lved

in p

rogr

essi

on o

f pr

osta

te c

ance

rV

aram

bally

et a

l.

Pros

tate

can

cer i

s a

lead

ing

caus

e of

can

cer-r

elat

ed d

eath

in m

ales

and

is

seco

nd o

nly

to lu

ng c

ance

r. A

lthou

gh e

ffect

ive

surg

ical

and

radi

atio

n tre

atm

ents

exi

st fo

r clin

ical

ly lo

caliz

ed p

rost

ate

canc

er, m

etas

tatic

pro

stat

e ca

ncer

rem

ains

ess

entia

lly in

cura

ble.

Her

e w

e sh

ow, t

hrou

gh g

ene

expr

essi

on p

rofil

ing,

that

the

poly

com

b gr

oup

prot

ein

enha

ncer

of z

este

hom

olog

2 (E

ZH2)

is o

vere

xpre

ssed

in h

orm

one-

refra

ctor

y, m

etas

tatic

pr

osta

te c

ance

r. …

Dys

regu

late

d ex

pres

sion

of E

ZH2

may

be

invo

lved

in th

e pr

ogre

ssio

n of

pro

stat

e ca

ncer

, as

wel

l as

bein

g a

mar

ker t

hat d

istin

guis

hes

indo

lent

pro

stat

e ca

ncer

from

thos

e at

risk

of l

etha

l pro

gres

sion

.

8

29

From

egg

to e

mbr

yo

?

30

31M

CB

140

11/

29/0

6

Hom

eotic

mut

atio

ns (W

. Bat

eson

)

“…N

ot th

at th

ere

has

mer

ely

been

a c

hang

e, b

ut th

at

som

ethi

ng h

as b

een

chan

ged

into

the

liken

ess

of s

omet

hing

el

se.”

Gen

etic

s

Alle

le

Het

eroz

ygou

s

Hom

ozyg

ous

32M

CB

140

11/

29/0

6

wt

ante

nnap

edia

9

33M

CB

140

11/

29/0

6

34

The

segm

enta

tion

hier

arch

y

35M

CB

140

11/

29/0

6

“Do

you

have

any

idea

who

I th

ink

I am

?!!”

1.S

egm

ent i

dent

ity is

det

erm

ined

by

trans

crip

tion

fact

ors.

2.Th

ey a

ct o

n ta

rget

gen

es o

nly

trans

ient

ly. T

hen

they

go

away

, and

the

activ

ity o

f the

ir ta

rget

s is

m

aint

aine

d by

larg

e co

mpl

exes

: Pol

ycom

b re

pres

ses

gene

s, a

nd T

ritho

rax

activ

ates

them

.3.

Nob

ody

knew

how

Pol

ycom

b an

d Tr

ithor

ax d

o th

is.

36M

CB

140

11/

29/0

6

How

Pol

ycom

b an

d Tr

ithor

ax w

ork

10

37M

CB

140

11/

29/0

6

extra

sex

com

bs

enha

ncer

of z

este

38M

CB

140

11/

29/0

6

E(z

) doe

s it

Post

ed S

epte

mbe

r 13,

200

2 –

CEL

L im

med

iate

ear

ly p

ublic

atio

n

Cze

rmin

, B.,

Mel

fi, R

., M

cCab

e, D

., S

eitz

, V.,

Imho

f, A

., an

d P

irrot

ta, V

. D

roso

phila

Enh

ance

r of Z

este

/ES

C c

ompl

exes

hav

e a

hist

one

H3

met

hyltr

ansf

eras

eac

tivity

that

mar

ks c

hrom

osom

al P

olyc

omb

site

s.

Cel

l. P

ublis

hed

onlin

e S

epte

mbe

r 13,

200

2.

10.1

016/

S009

2867

4020

0975

3

Mül

ler,

J., H

art,

C.M

., Fr

anci

s, N

.J.,

Var

gas,

M.L

., S

engu

pta,

A.,

Wild

, B

., M

iller,

E.L

., O

'Con

nor,

M.B

., K

ings

ton,

R.E

., an

d S

imon

, J.A

. H

isto

ne m

ethy

ltran

sfer

ase

activ

ity o

f a D

roso

phila

Pol

ycom

b gr

oup

repr

esso

r com

plex

. Cel

l. P

ublis

hed

onlin

e S

epte

mbe

r 13,

200

2.

10.1

016/

S009

2867

4020

0976

5

39M

CB

140

11/

29/0

640

MC

B 1

40 1

1/29

/06

“Influ

entia

l ide

as a

re a

lway

s si

mpl

e. S

ince

nat

ural

ph

enom

ena

need

not

be

sim

ple,

we

mas

ter t

hem

, if

at a

ll, b

y fo

rmul

atin

g si

mpl

e id

eas

and

expl

orin

g th

eir

limita

tions

.”

Al H

ersh

ey

11

41M

CB

140

11/

29/0

6

Reg

ulat

ion

of g

enes

occ

urs

via

the

inte

ract

ion

of tr

ans-

actin

g fa

ctor

s (p

rote

ins)

with

cis

-act

ing

sequ

ence

s ne

ar th

e ge

nes

them

selv

es.

+st

imul

us

+

42M

CB

140

11/

29/0

6

4344

Bic

oid

is th

e an

terio

r m

orph

ogen

12

45M

CB

140

11/

29/0

646

MC

B 1

40 1

1/29

/06

Wha

t dem

ocra

cy, I

mea

n, g

ene

regu

latio

n, is

real

ly li

ke•

Tran

s-ac

ting

fact

ors

do n

ot d

istri

bute

in th

e nu

cleu

s ba

sed

on th

e pr

imar

y se

quen

ce o

f the

gen

ome:

som

e fa

ctor

s fa

il to

bin

d m

ost g

enes

that

hav

e se

quen

ces

wai

ting

for t

hem

, and

oth

er fa

ctor

s bi

nd a

larg

e nu

mbe

r of

gen

es th

at d

o N

OT

have

seq

uenc

es fo

r the

m•

Eve

n w

hen

a fa

ctor

bin

ds n

ext t

o a

gene

, man

y tim

es,

noth

ing

happ

ens;

the

sam

e fa

ctor

bou

nd to

two

diffe

rent

ge

nes

can

exer

t dia

met

rical

ly o

ppos

ite e

ffect

s•

Mos

t gen

es in

the

hum

an g

enom

e ar

e un

der

cons

ider

able

regu

lato

ry in

fluen

ce fr

om e

ntiti

es o

ther

than

“s

impl

e” tr

ans-

actin

g fa

ctor

s; th

ese

entit

ies

incl

ude

nonc

odin

g R

NA

and

mod

ified

his

tone

s

47M

CB

140

11/

29/0

6

Boy

er a

nd Y

oung

C

ell S

ept.

23, 2

005

Fisc

hle,

Wan

g, A

llis

CO

CB

200

3

Dav

id A

llis: “

the

hist

one

code

”

13

51M

CB

140

11/

29/0

6

1963

-200

020

00 -

…

Hen

ry e

t al.

(11/

1/20

03) G

enes

Dev

. 17:

264

8.

Gen

etic

info

rmat

ion

Lac

oper

ator

gaat

tgtg

agcg

gata

acaa

ttt

14

Gen

etic

info

rmat

ion

Gen

etic

info

rmat

ion

-

+?