Regulation of KDM5 by multiple cofactors regulates cancer and stem cells

Regulation of Regulation of histone histone

modifications and modifications and neural neural

differentiationdifferentiationChristopher WynderChristopher Wynder

Autism, Cancer and Autism, Cancer and neurogenesisneurogenesis

During 1During 1stst 2 years ASD 2 years ASD brains “over-grow”brains “over-grow”

This leads to hyper-This leads to hyper-connectivityconnectivity

Often this hyper-Often this hyper-connectivity leads to connectivity leads to apoptosisapoptosis

This results in the This results in the absence of neurons absence of neurons

ASD can also result ASD can also result from later synaptic from later synaptic activity changesactivity changes

Courchesne, Neuron 56 (2007)

Many of the ASD Many of the ASD genes are also genes are also cancer relatedcancer related

Epigenetics is Epigenetics is given as the reason given as the reason for ASDfor ASD

Recently Recently mutations in mutations in multiple epigenetic multiple epigenetic regulators have regulators have been found in ASD been found in ASD patientspatients

Epigenetic definitionEpigenetic definition

““Non-genetic events” which result in Non-genetic events” which result in stable and inheritablestable and inheritable gene expression gene expression patterns.patterns.

Epigenetic changes are LONG term Epigenetic changes are LONG term changes, not necessarily related to changes, not necessarily related to histone mediated transcriptional controlhistone mediated transcriptional control

Particularly relevant during Particularly relevant during developmentdevelopment

Regulation of histone modifications are a Regulation of histone modifications are a significant and significant and changeablechangeable example of example of an epigenetic modification.an epigenetic modification.

What is the relationship What is the relationship between transcriptional between transcriptional

regulation by histone regulation by histone modifications and epigenetic modifications and epigenetic

events?events?

Maintaining expression of Maintaining expression of genes during genes during

differentiationdifferentiation

Gene regulation is divided into 2 sub-regions, Gene regulation is divided into 2 sub-regions, regulatory and ORF (gene encoding)regulatory and ORF (gene encoding)

In general, histone modification of the ORF is a In general, histone modification of the ORF is a on/off mark due to the absolute requirement of on/off mark due to the absolute requirement of these marks for RNA Polymerase accessthese marks for RNA Polymerase access

Histone modifications in the promoter generally Histone modifications in the promoter generally are the “tuner” increasing the amount of mRNA are the “tuner” increasing the amount of mRNA made.made.

Histone H3modifications

Step-wise acclimation of histone Step-wise acclimation of histone modifications regulate modifications regulate

developmentdevelopment

3meH3K4

RPolIII

Low read through rate, low amounts of mRNA made, therefore low amounts protein, allows the cell to block the expression of cell lineage genes without 2nd signal.

Extremely low to no read through.3meH3K27

HDM: KDM5(s)HMT:KMT6

HDM: KDM6(s)HMT:KMT2(s)

KDM5b (aka JARID1b/PLU1)

Adapted from Shilatifard Ann.Biochem 2006

Linking biochemistry to Linking biochemistry to biological propertiesbiological properties

1.1. KDM5b-What role does it play in KDM5b-What role does it play in neural differentiationneural differentiation

2.2. How do you activate its How do you activate its enzymatic activity (regulation of enzymatic activity (regulation of KDM5 function)KDM5 function)

3.3. How is KDM5 targeted to How is KDM5 targeted to specific genes (recruitment of specific genes (recruitment of specific KDM5 proteins)specific KDM5 proteins)

KDM5b and KDM5b and transcriptional controltranscriptional control

K4MeMeMe X

MeMeMe

KDM5BKDM5B

KDM5BKDM5B

Upregulated in breast and prostate cancer

Overexpression of KDM5b leads to: Increased Proliferation Block in terminal differentiation

K4KDM5BKDM5B

KDM5b regulates Cell Cycle KDM5b regulates Cell Cycle speed and exit in stem cellsspeed and exit in stem cells

p27

p27 transcription

CyclinE

p27

CyclinA

p27 transcription

Differentiation

Dey et al MCB 2008

Recycling of cell cycle Recycling of cell cycle genes during neural genes during neural

differentiationdifferentiation

Frank and Tsai, Neuron 62 (2009)

p21CIP1 p57Kip2 p27Kip1

*

**

KDM5b blocks terminal KDM5b blocks terminal differentiation but not cell differentiation but not cell

lineage choicelineage choice

Neural Differentiation

Sox1DAPI

100 um

Sox1DAPI

Cont

rol

KDM5b

Dey et al MCB 2008

Regulating the Regulating the regulatorsregulators

ApoptosisPro-neural

Pro-self renewal

Pro-neural

self renewal

Stage specific:Seq. specific TFs:

Oct4, Sox2, FoxD3 NeuroD2, Sox1, FoxG1 Sox17, NGN2 Sox1, FoxD3

PluripotentStem Cell

Neural Stem/Progenitor

DifferentiatedNeuron

NeuralStem Cell

Ubiquitous factorsChromatin/histone Regulators:

KDM5b, Ring6a KDM5b,KDM5c Ring6a

Ring6a, KDM5c,iBRAF, MLL

KDM5b, Ring6a,

Regulating the Regulating the regulatorsregulators

ApoptosisPro-neural

Pro-self renewal

Pro-neural

self renewal

Stage specific:Seq. specific TFs:

Oct4, Sox2, FoxD3 NeuroD2, Sox1, FoxG1 Sox17, NGN2 Sox1, FoxD3

PluripotentStem Cell

Neural Stem/Progenitor

DifferentiatedNeuron

NeuralStem Cell

Ubiquitous factorsChromatin/histone Regulators:

KDM5b, Ring6a KDM5b,KDM5c Ring6a

Ring6a, KDM5c,iBRAF, MLL

KDM5b, Ring6a,

How do you control Ubiquitous factors How do you control Ubiquitous factors to modulate specific events?to modulate specific events?

Harvest spheres for RT-PCR and ChIP

Represents “Day 1” of neurodifferentiation assay

Harvest Day 3

Harvest Day 14

Harvest Day 10

Harvest Day 8Harvest Day 6

Harvest Day 5

Harvest Day 4

Mainly Neural Stem

Completely Differentiated

mESCs or hu iPSCs

Testing epigenetic Testing epigenetic mechanismsmechanisms

1

2

3

This in vitro assay can be used with hu iPSCs, ESCs (both human and mouse), Neural stem cells (neurospheres), mammospheres and prostate stem cells

This assay can also be combined with the qHDM and kinetic HDM assay



Harvest Day 3

Harvest Day 14

Harvest Day 10


Harvest Day 5

Harvest Day 4

Mainly Neural Stem


mESCs or hu iPSCs


1

2

3

KDM5 proteins are often found at active KDM5 proteins are often found at active promoters.promoters.

All HDMs require co-factors for in vivo All HDMs require co-factors for in vivo activity. Usually in a single multi-subunit activity. Usually in a single multi-subunit complexcomplex

KDM5s have a novel 2 component system:KDM5s have a novel 2 component system:

1.1. TLE4TLE4: Activation co-factor for enzymatic : Activation co-factor for enzymatic activityactivityGene repressionGene repression

2.2. BHC80BHC80: Recruitment of KDM5 to gene : Recruitment of KDM5 to gene targets is separate based on landmarkstargets is separate based on landmarks

KDM5s are regulated by KDM5s are regulated by 2 part system2 part system

KDM5b

TLE4

TSS

KDM5s are regulated by 2 KDM5s are regulated by 2 part systempart system

Activation

*

*

0

5

10

15

20

25

1

Fol

d en

richm

ent

ver

sus

IgG

p27 promoter

IgG KDM5bTLE4

TLE4 is pulled down by TLE4 is pulled down by KDM5bKDM5b

Q GP CcNCcN SP WD-Repeat TLE4 domain structureTLE4 domain structure

KDM5b

Contro

l (s)

TLE4

IP:

KDM5b

TLE4

Input

170

70

100

55

IgG

TLE4

KDM5b

- 1 1 2 0.5 0.25 0

1 0 1 1 1 1 0

Addition of KDM5b Addition of KDM5b increases 3meH3K4 increases 3meH3K4

binding of TLE4binding of TLE4

TLE4 alone interacts specifically with 3meH3K4 containing nucleosomesin binding assays.This is increased in the presence of KDM5b.Similar binding is seen with KDM5d

3meH3K4

Histone H3(loading control)

Q GP

CcNCcN SP WD-Repeat

TLE4 is necessary and TLE4 is necessary and sufficient for KDM5 NDM sufficient for KDM5 NDM

activityactivity

**

**

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

r.TLE4

r.KDM5b - + - +

- - + +

Fold

Cha

nge

in 3

meH

3K4

r.KDM5d

1

**

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

yKDM5 yKDM5r.TLE4

*

NDM assay – nucleosomal demethylase [surrogate for in vivo activity]

TLE4 complex has H3K4 HDM TLE4 complex has H3K4 HDM activity in vivoactivity in vivo

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

No KDM5b R.KDM5B TLE4 IP-mESCs

Histones

Chromatin

EYFP TLE4 T-Dom-Neg50 um

50 um

Day 4

Day 7

TLE4 alters terminal TLE4 alters terminal differentiationdifferentiation

Sox1 persist in TLE4 Sox1 persist in TLE4 expression cellsexpression cells

EYFP TLE4

Sox1TLE4

Sox1EYFP

Sox1CCNSP

20 um

T-DNegDay 10

*

**

0123456789

10

Day 4

Fo

ld c

ha

ng

e in

nu

mb

er

of

sph

ere

s fo

rme

d

n=3

TLE4Control

**

**

0%

20%

40%

60%

80%

100%

120%

140%

160%

1

Fo

ld c

ha

ng

e in

nu

mb

er

of

sph

ere

s p

late

d

n=3

TLE4Control

TLE4 affects sphere TLE4 affects sphere propertiesproperties

T-DNeg T-DNeg

Quantification of Day 4 sphere properties

**

0

0.5

1

1.5

2

2.5

Syn AFF1 PLAGL1

Control

TLE4

Fo

ld c

ha

ng

e in

bin

din

g t

o P

LA

GL

1 p

rom

ote

r

Fol

d ch

ange

in m

RN

AR

T-P

CR

*

*0

2

4

6

8

10

12

3meH3K4 KDM5b TLE4

Ctrl

TLE4

Lineage markers Differentiation

marker

ChIP

Modulation of TLE4 alters Modulation of TLE4 alters neural differentiationneural differentiation

RT-PCR PLAGL1-Day 4 after T D-Neg

**

0

1

2

3

4

5

6

7

8

9

Control CCNSP

ChIP 3meH3K4 and KDM5bPLAGL1-Day 4 after T D-Neg

Fo

ld c

ha

ng

e in

bin

din

g t

o P

LA

GL

1 p

rom

ote

r

Fo

ld c

ha

ng

e in

tr

an

scrip

tion

0.2**

*

0

5

10

15

20

25

30

35

3meH3K4 KDM5b TLE4

Control

CCNSP

**

*

H3

H4 H2A

H2BK4 K43K43

H3

H4 H2A

H2BK4

meme

me

Stem Cell

Cell cycle inhibitor

?

PluripotentSelf-renewing, proliferative

H3

H4 H2A

H2BK4

meme

me

H3

H4 H2A

H2BK4

meme

me

Multipotent Proliferative

e.g. Neural stem cellNaïve T cells

Stem Cell


KDM5b

KDM5b

Lineage Committed e.g. neuronCD4+ Th1

H3

H4 H2A

H2BK4

meme

me


H3

H4 H2A

H2BK4 K43K43

Stem Cell?

KDM5b recruitment and KDM5b recruitment and activationactivation

Data from differentiation studies showed KDM5b was localized to active genesBUT was not active.

Suggests an independent recruitment and activation mechanism

Mammalian homologues?Mammalian homologues?

KDM5

TLE(s)

Moshkin et al, Mol. Cell 2010

In Drosophila KDM5Is localized by interaction of the NAP1-PF1 complex with Gro-CtBP

PHF12 Also PHF14 & BHC80

KDM5 associated proteinsKDM5 associated proteins

680500250

880

100

PHD

PHD PHD

BHC80

PHF14

720

PHD PHDdPF1

Interacts with and recruits dro KDM5

Mammalian paralogues (PHF12 is homolog)

PHD domain proteins PHD domain proteins recruit KDM5srecruit KDM5s

Both BHC80 and PHF14 can Both BHC80 and PHF14 can increase KDM5b localization in increase KDM5b localization in mESCs to specific loci (sim. To PF1)mESCs to specific loci (sim. To PF1)

The effects on transcription are The effects on transcription are variablevariable

PHD domain proteins are NOT PHD domain proteins are NOT responsible for enzymatic activation responsible for enzymatic activation (sim to PF1)(sim to PF1)

KDM5b interacts with KDM5b interacts with multiple PHD domain multiple PHD domain

proteins in ESCsproteins in ESCsIP: KDM5b BHC80 KMT2a

B-actin(INPUT)

BHC80

KDM5bTransfected: EGFP KDM5b Phf14V5

+KDM5bV5 IP: + + +

KDM5b

ECFP-BHC80 ECFP-PHF14

PHF14

K4K4

BHC80KDM5

TLE4

TSS


ActivationActivation Gene Specific RecruitmentGene Specific Recruitment

BHC80: key element in BHC80: key element in gene target choicegene target choice

680500250100

PHDBHC80

BHC80 originally described as part of the KDM1 H3K4 demethylase complexBHC80 originally described as part of the KDM1 H3K4 demethylase complex

Green is common to KDM5b interacting PHFsGreen is common to KDM5b interacting PHFs

Purple is a evolutionarily conserved region.Purple is a evolutionarily conserved region.

The PHD domains are also highly conservedThe PHD domains are also highly conserved.

Yellow is a putative GSK3 phospho site

BHC80 regulates global BHC80 regulates global H3K4 methylationH3K4 methylation

ECFP-BHC80 3meH3K4 Merge

BHC80 mediates ESC BHC80 mediates ESC differentiation by removing differentiation by removing

KDM5b KDM5b

3meH3K4

DAPI

KDM5b

KDM5b

HistoneH3

mESC mESCBHC80

ChromatinFraction

IP: KDM5b BHC80 KMT2a

B-actin(INPUT)

BHC80

KDM5b

BHC80 complex(es).BHC80 complex(es).

BHC80-v

5

Ring6a

BHC80

Par-3

hnRNPB1

MeK43-H2B

Western Blot

Ring6a-Initially found as a co-factor for KDM5d HDM activity. Also interacts with Ring1a (H2A Ub-ligase)

H2B-H2B found in BHC80 complex appeared to methylatedSuggests that BHC80 binds H2B?

Ac-H3

R6a

0

2

4

6

8

10

12

3meHK43 H2A H2B H3

H2B

BHC80 has gene specific BHC80 has gene specific affectsaffects

*

*

0

0.2

0.4

0.6

0.8

1

1.2

1.4

RNA 3meK4 KDM5b

Ctrl

sh80

mTCF3 p27

**

0

0.5

1

1.5

2

2.5

3

3.5

4

RNA 3meK4 KDM5b

Ctrlsh80

*

***

0

0.5

1

1.5

2

2.5

3

RNA 3meK4 KDM5b

Ctrl

sh80

Egr1

n=3n=3n=3

sh80

BH

C80

OX

P

0

0.5

1

1.5

2

2.5

RNA 3meH3K4 KDM5b BHC80

ControlBHC80

N.D.

0

0.5

1

1.5

2

2.5

RNA 3meH3K4 KDM5b BHC80

ControlBHC80

K4K4

BHC80KDM5

TLE4

TSS


ActivationActivationGene Specific RecruitmentGene Specific Recruitment

K43

meme

H2B

Why methylate Why methylate K43(H2B)?K43(H2B)?

Block or enhance H2B K123 Block or enhance H2B K123 ubiquitinationubiquitination

Crosstalk with H3 methylationsCrosstalk with H3 methylations

•Does 2meK43 correlate with Does 2meK43 correlate with transcription?transcription?•What is the role of 2meK43-H2B in What is the role of 2meK43-H2B in stem cells?stem cells?•Does BHC80 bind to 2meK43-H2B?Does BHC80 bind to 2meK43-H2B?

*

*

***

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

mTCF3 BMI1 BRCA1 p27 Oct4 Nanog PLAGL1

H2B WT

H2B K43A

transient

Fol

d ch

ange

in t

rans

crip

tion

Acute loss of K43 Acute loss of K43 methylation triggers methylation triggers

transcriptional repressiontranscriptional repression

Flag (loading control)

Ubiquitin

3meH3K4

Histone H3

3XFlH2BmESC

3XFlK43A-mESC

NucleosomeIP:

3Xflag-H2BmESC3Xflag-H2BK43A

2meK43-H2B is required 2meK43-H2B is required for cell fate decisionsfor cell fate decisions

Neural differentiation (1% serum,B27, DMEM)1% Gelatin

KDM5b

2meK43H2B

3XflagH2BH2B

3XFlH2BmESC

3XFlK43A-mESC

3XFlH2BNS

3XFlK43A-

NS

Flag M2

K43 is enriched in K43 is enriched in progenitors but not stem progenitors but not stem

cellscells

Doublecortin2meK43 H2B

Nose tail

Phospho-H32meK43 H2B

TUJ12meK43 H2B

2meK43 H2B Dorsal Root ganglia

Loss of K43 methyl shows Loss of K43 methyl shows increased KDM5b increased KDM5b

associationassociation

Fo

ld c

ha

ng

e in

DN

A b

ind

ing

0

2

4

6

8

10

12

p27 PLAGL1 Nanog mTCF3

3XFL H2B incorporation

0

0.5

1

1.5

2

2.5

3


3XFL K43A incorporation

**

**0

1

2

3

4

5

6


H2B WTH2B K43A

n=3

Fo

ld c

ha

ng

e in

tra

nsc

riptio

n

1o Flag then Re-ChIP KDM5b

B.D. B.D.

*

*

0

2

4

6

8

10

12

14

p27 PLAGL Nanog mTCF3

H2B

K43A

n=3

Fo

ld d

iffe

ren

ce in

a

sso

cia

tion

with

H2

B/H

2B

K4

3A

0

0.5

1

1.5

2

2.5

RNA KDM5b 2meK43 3meH3K4 acetyl BHC80

Control

BHC80

Egr1

Fo

ld c

ha

ng

e c

om

pa

red

to

co

ntr

ol l

ine

B.D.

**

n=3

0

1

2

3

4

5

6

7

RNA KDM5b 2meK43 3meH3K4 acetyl BHC80

Control

BHC80

p27

*

*

*

B.D.

n=3

B.D.

K43 methylation is related K43 methylation is related to KDM5b recruitment but to KDM5b recruitment but

not transcriptionnot transcriptionP

eptid

e bo

und

to B

HC

80

0

0.2

0.4

0.6

0.8

1

1.2

1.4

3meH3K4 3meH3K4:0meH3K4 2meH2B 2meH2B:0meH2B

3meH3K4

3me:0meH3K4

2meK43 H2B

2me:0meH2B

Detection of 3meH3K4

Detection of 2meK43 H2B

**n=3

BHC80 binding to methyl K43 is not altered by unmethylated K43

KDM5b preferentially KDM5b preferentially demethylates K43.demethylates K43.

0

0.2

0.4

0.6

0.8

1

1.2

1.4

meK43 H2B meK43+H2B tail meK43+0meH3K4 2meK43+3meH3K4

meK43 H2B

r.KDM5B

In vitro HDM assay peptide competition BHC80 blocks 2meK43 demethylation in a histone H3 tail dependent manner

**

**

0

0.2

0.4

0.6

0.8

1

1.2

1.4

meK43 H2BPeptide r.KDM5b r.KDM5b+BHC80

r.KDM5b+BHC80+0meH3K4

r.KDM5b+BHC80+3meH3K4

2meK

43 p

eptid

e F

old

chan

ge

*

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1

Control KDM5bGlobal 2meK43(H2B) levels during neural differentiation are diminished by transfection of

KDM5b

n=3

KDM5b 2meK43 KDM5b 2meK43 demethylation blocked by demethylation blocked by

TLE4TLE4

2meK43H2B

Pan H3

TLE4

KDM5b alone can demethylate 2meK3H2B in nucleosomes.TLE4 inhibits this activity

**

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Control r.KDM5b 5b+r.TLE4 5b+r.T-WD

N=6

K4

H3 H2B

meme

K43

TLE

4

me

meme

BHC80

TSS

meme

me

meme

Loss of H2B (K43) Loss of H2B (K43) methylation triggers methylation triggers

3meH3K4 loss3meH3K4 loss

K4K4

me

H3 H2B

meme

K43K43

meme

BHC80

KDM5b

TLE4

TSS


Wnt/GSK3Notch

Wnt/GSK3Stats/CK2

NGF/Erk2Steroidscatabolism

Linking biochemistry to Linking biochemistry to biological properties-biological properties-

Future directionsFuture directions1.1. Define structure-function Define structure-function

relationship between KDM5s and relationship between KDM5s and co-factors (co-factors (in vitro reconstitutionin vitro reconstitution))

2.2. Define the cell biology that is Define the cell biology that is altered by modulation of this system altered by modulation of this system ((Disease specific iPSCs and Disease specific iPSCs and ESCsESCs))

3.3. What is the role of these proteins in What is the role of these proteins in neural development (neural development (mouse mouse modelsmodels))

K4K4

me

K4K4

me

meme

meme

K43K43

meme

K43K43

meme

BHC80

KDM5

TLE4

TSS

Molecular Interrogation Molecular Interrogation KDM5 activityKDM5 activity

1. How does BHC80 choose the which KDM5

2. Is the interaction antagonistic

3. How general is this model i.e. how many other recruiters are there?

1. How is TLE4 recruited to KDM5 loci?

2. What is the role of Post-translation modifications in TLE4 localization

Syn Ab/CcNSP construct

K4K4

me

K4K4

me

meme

meme

K43K43

meme

K43K43

meme

BHC80

KDM5

TLE4

TSS


1. How does BHC80 choose the which KDM5

2. Is the interaction antagonistic

3. How general is this model i.e. how many other recruiters are there?

K4K4

me

K4K4

me

meme

meme

K43K43

meme

K43K43

meme

BHC80

KDM5

TLE4

TSS


1. How is TLE4 recruited to KDM5 loci?

2. What is the role of Post-translation modifications in TLE4 localization

Syn Ab/CcNSP construct

Understanding how KDM5 Understanding how KDM5 activity is integrated into activity is integrated into

cell functioncell function

C.C. Inhibitors Differentiation Cell lineage

GSK3/Erk BHC80

Ring6a

J1b

KMTx

K43K43

MeMe

OROR

BHC80

TLE4TLE4TLE4

Understanding how KDM5 Understanding how KDM5 activity is integrated into activity is integrated into

cell functioncell function

C.C. Inhibitors Differentiation Cell lineage

GSK3/Erk BHC80

Ring6a

J1b

KMTx

K43K43

MeMe

OROR

BHC80

TLE4TLE4TLE4

Block interactionTest affect during

neural diff.(Breast or Prostate)

Block interactionTest affect during

neural diff.(Breast or Prostate)



Harvest Day 3

Harvest Day 14

Harvest Day 10


Harvest Day 5

Harvest Day 4

Mainly Neural Stem


mESCs or iPSCs


1

2

3



Harvest Day 3

Harvest Day 14

Harvest Day 10


Harvest Day 5

Harvest Day 4

Mainly Neural Stem


mESCs or iPSCs


1

2

Abrogation of KDM5/Co-factor here to elucidate the role of this complex in acquisition of neural lineage.

Epigenetics of differentiation, can transient expression block/enhance terminal differentiation

(can use adult sphere forming cells including Breast, Prostate from human/mouse)

3Cell lineage selection; can expression during terminal differentiation, modify the type of neuron that is made

ORCause de-differentiation/proliferation (iPSC/Cancer)

AcknowledgementsAcknowledgementsLeanne Stalker Leanne Stalker

(CBCF)(CBCF)Bijan DeyBijan DeySean KeatingSean Keating

Ramin ShiekhattarRamin ShiekhattarJoyce Papadimitriou-TaylorJoyce Papadimitriou-Taylor

Jonathan BramsonJonathan Bramson•Willa LiaoWilla Liao•Ajapal BhanguAjapal Bhangu

Martin DoughtyMartin DoughtyMin Gyu LeeMin Gyu LeeMarc MeneghiniMarc MeneghiniSachdev SidhuSachdev Sidhu

Ray TruantRay TruantLise MunsieLise Munsie

Regulation of KDM5 by multiple cofactors regulates cancer and stem cells

Science

Transcript of Regulation of KDM5 by multiple cofactors regulates cancer and stem cells