social regulation of gene expression - stanford medicine · social regulation of gene expression...

Social regulation of gene expression

Steve W. Cole, Ph.D.UCLA School of Medicine

Division of Hematology-Oncology

Lonely

Integrated

Social isolation

78131

Inflammation

Immunoglobulin G1 productionType I interferon antiviral response

Cole et al. Genome Biology 2007

Low SESSocial loss / bereavementPost-traumatic stressCancer diagnosisSocial threatLonelinessSocial instabilityChronic stressLow social rankCaregiving for seriously illAnxietyEarly life adversity

Social instability

Cole et al. PNAS 2012Tung et al. PNAS 2012Cole et al. PNAS 2015

Snyder-Mackler et al. Science 2016Korytar el al. Frontiers Immunol 2016

Socialprocesses

CNSfunction

Genome

Social signal transduction

Lonely

Integrated

78131

Social isolation

Genome

Socialprocesses

CNSfunction

Peripheralneurobiology

Cell signal transduction

Transcriptionfactors

Simple questions1. Which gene modules are

sensitive to social processes?

2. Which transcription control pathways mediate those effects?


Irwin & Cole, Nature Reviews Immunology 2011

CNS threat perception

SNS neurons, NE

Bone marrow

StemCell

Lymphoid

Myeloid

Granulocyte

Monocyte

Systemic circulation

Cole et al. PNAS 2011Powell et al. PNAS 2013

Heidt et al. Nature Medicine 2014Cole et al. PNAS 2015

GW2580

Sloan et al. Cancer Research 2010Cole et al. Nature Reviews Cancer 2015

Adverseenvironment

CNS threat perception

SNS neurons, NE

Bone marrow

StemCell

Lymphoid

Myeloid

Granulocyte

Monocyte

Systemic circulation

Lung / airway- pneumonia

- asthmaVasculature

- atherosclerosis

Solid tumor- breast - ovarian

Metastasis

Lymph nodes- neoinnervation- IFN, Th2/Th17

Viralinfection

CNS- inflammation- neurodegen

Cole et al. PNAS 2011Powell et al. PNAS 2013

Heidt et al. Nature Medicine 2014Cole et al. PNAS 2015

Irwin & Cole, Nature Reviews Immunology 2011Cole, PLoS Genetics 2014

CTRA – conserved transcriptional response to adversity

Immunoglobulin G1 productionType I interferon antiviral response

Mother reared

Peer reared

717521

Inflammation

Irwin & Cole, Nature Reviews Immunology 2011Cole, PLoS Genetics 2014

2 “social genomic programs” in immune cells

safe/attached danger/isolated

Lonely

Integrated

How not to live

How should we live?

How often do you feel happy?How often do you feel satisfied?

Life has direction and meaning?

Grow and become a better person?

Hedonic Eudaimonic

Fredrickson et al. PNAS 2013

FOSFOSBFOSL1FOSL2JUNJUNBJUNDNFKB1NFKB2RELRELARELB

Eudaimonic

Hedonic

IL1AIL1BIL6IL8TNFPTGS1PTGS2

IGJ IGLL1 IGLL3

GBP1 IFI16 IFI27 IFI27L1 IFI27L2 IFI30 IFI35 IFI44 IFI44L IFI6 IFIH1 IFIT1 IFIT1L IFIT2 IFIT3 IFIT5

IFITM1 IFITM2 IFITM3 IFITM4P IFITM5 IFNB1 IRF8 IRF2 IRF7 MX1 MX2 OAS1 OAS2 OAS3 OASL

Favorable

Adverse

Fredrickson et al. PNAS 2013

HedonicEudaimonic

Hedonic

Eudaimonic

Amygdala

Ventral Striatum

Dutcher, Bower, Eisenberger, et al. in prep 2016Eisenberger & Cole, Nature Reviews Neuroscience 2012

‐0.3

‐0.2

‐0.1

0

0.1

0.2

0.3

‐2 ‐1 0 1 2

r = ‐.71

VS activation

ProinflammatoryRN

A (lo

g 2)

‐0.3

‐0.2

‐0.1

0

0.1

0.2

0.3

‐2 ‐1 0 1 2

r = +.11

Amygdala activation

ProinflammatoryRN

A (lo

g 2)

Goetz et al. Psychological Bulletin 2010Porges Int J Psychophysiology 2001

Porges Psychophysiology 1995

Goetz et al., Psychological Bulletin 2010Porges, Int J Psychophysiology 2001

Porges, Psychophysiology 1995

How to make more eudaimonia?

‐0.14‐0.12‐0.10‐0.08‐0.06‐0.04‐0.020.000.020.040.060.080.100.120.14

Control

World

Other

Self

∆ C

TRA

gene

exp

ress

ion

log 2

[ pro

infla

mm

ator

y–

(inte

rfero

n &

antib

ody)

]

* Others vs Control: p = .0162Others vs 0: p = .0039

*

Lyubomirsky et al. under review 2016

Profile plot

ControlTrack activities

x 4 weeksn = 35

Other3 kind acts/day

x 4 weeksn = 33

World3 kind acts/day

x 4 weeksn = 45

Self3 kind acts/day

x 4 weeksn = 42

155 healthy adultsUC Riverside community

Creswell et al. BBI 2012Antoni et al. Biological Psychiatry 2012

Black et al. Psychoneuroendocrinol 2013Bower et al. Psychoneuroendocrinol 2014

Irwin et al. JNCI Monographs 2014Bower et al. Cancer 2015

Laudenslager et al. J Behav Med 2016

Fredrickson et al. PNAS 2013Cole et al. Psychoneuroendocrinol 2015

Fredrickson et al. PLOS One 2015 Kitiyama et al. Psychoneuroendocrinol 2016

Lyubomirsky et al., under review 2016

Collado-Hidalgo et al. BBI 2006Sloan et al. Cancer Res 2010

Powell et al. PNAS 2013Lavretsky et al. under review 2016

Ben-Eliyahu et al. in preparation 2016Capitanio et al. in preparation 2016

Genome

Socialprocesses

CNSfunction





1. Recursive persistence and environmental embedding

Not-so-simple questions

Simple questions1. Which gene modules are

sensitive to social processes?

2. Which transcription control pathways mediate those effects?

Stable social conditions

Unstable

Sloan et al. Journal of Neuroscience 2007Capitanio & Cole Philos Trans R Soc Lond B Biol Sci. 2015

Cole et al. PNAS 2015

NG

Fm

RN

A (fo

ld-d

iffer

ence

)

0.0

1.0

2.0

3.0

Social stress-. +

NGF expression IFNB mRNA

IFN

Bm

RN

A (

% p

re-s

tudy

bas

elin

e)

- +Social Stress

p = .0020

20

40

60

80

100

120

0

140

Genome

Socialprocesses

CNSfunction




Recursive persistence


0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

78

910

11

Age (yrs)

Expr

essi

on (l

og2)

Genomic resilience to early adversity?

681 Diverged by mo. 6650 Recovered – 95%31 Embedded – 5%

Recovered?Or Embedded?

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

78

910

11

Age (yrs)

Expr

essi

on (l

og2)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

78

910

11

Age (yrs)

Expr

essi

on (l

og2)

Suomi et al. unpublished 2016

IFI2

7m

RN

A (lo

g 2)

Age (years)

Peer-reared

Instability/sensitivity:1.2 vs. 3.2 critical points (d’), p < 10-10

1.9 vs. 3.7 inflection points (d’’), p < 10-10

Community-reared

Genome

Socialprocesses

CNSfunction





1. Recursive persistence and environmental embedding

2. Social programming of non-immune tissues (e.g., neural, reproductive)

3. The human metagenome

Not-so-simple questions

Behavior &Social Niche

Health

Socialprocesses

CNSfunction




Geneexpression

Social genomics

Health

Socialprocesses

CNSfunction




Geneexpression

Health

Socialprocesses

CNSfunction




Geneexpression

Health

Socialprocesses

CNSfunction




Geneexpression

Health

Socialprocesses

CNSfunction




Geneexpression

Health

Socialprocesses

CNSfunction




Geneexpression

Health

Socialprocesses

CNSfunction




Geneexpression

Socialprocesses

CNSfunction




Geneexpression

Socialprocesses

CNSfunction




Geneexpression

Socialprocesses

CNSfunction




Socialprocesses

CNSfunction




Health

Socialprocesses

CNSfunction




Geneexpression

Health

Socialprocesses

CNSfunction




Geneexpression

Your experiences todaywill influence the molecular composition of your body for the next 2-3 months

… or perhaps the rest of your life.

Plan your day accordingly.

CollaboratorsJohn Cacioppo, Louise Hawkley, Bob RoseGreg Miller, Edith ChenSteve Suomi, Gabriella Conti, James HeckmanSusan Lutgendorf, Anil SoodJohn Sheridan, Nicole PowellJohn Capitanio, Erica SloanBrian Knutson, Scott HallMichael Irwin, Patti Ganz, Julie BowerMargaret Kemeny, Jerry ZackTeresa Seeman, Andrew FuligniBarbara Fredrickson, Karen Grewen

SupportNCI CA116778, CA110793, CA109298 NIAID AI33259, AI36554, AI49135, AI52737NIA AG107265, AG033590, AG034679NIMH MH00820, MH15750NCRR RR020645UC Universitywide AIDS Research Program UCLA AIDS InstituteMacArthur FoundationJames Pendleton Charitable TrustSanta Fe Institute for Complex Systems Norman Cousins Center

The experienced self• stable• independent

The molecular self• fluid• permeable

Gene

Protein

IL6

RNA

DNA

Health

The experienced self• stable• independent

The molecular self• fluid• permeable

Environment

Gene

Protein

IL6

RNA

DNA

Health

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Civ

ilian

Chi

ld S

oldi

er

CPS

S

Low

Med

Low

Aver

age

Med

Hig

h

Hig

h

Resilience

CTR

A ge

ne e

xpre

ssio

nlo

g 2[ p

roin

flam

–(in

terfe

ron

&an

tibod

y) ]

Nepali former child soldiers

Nepal child soldier study PI: Dr. Brandon KohrtN = 254 blood sampled in 2013, at age 15-26 yrs, 46% female7 years out from war’s end in 200652% former child soldier (1/4 combat exposure), 48% civilian child control11% significant post-traumatic stress symptoms Kohrt et al. PNAS 2016

Eudaimonia & gene expression

DiscoveryFredrickson et al. (2013) PNAS, 110, 13684-13689

Confirmation & generalization Fredrickson et al. (2015) PLOS One, 10, e0121839

Eudaimonia vs. loneliness: who wins?Cole et al. (2015) Psychoneuroendocrinology, 62, 11-17

Purpose at workKitayama et al. (2016) Psychoneuroendocrinology, 75, 175-181

Eudaimonia & longevitySteptoe et al. (2015) The Lancet, 385, 640-648Hill & Turiano (2014) Psychological Science, 25, 1482-1487

Cultivating positive leukocytes

Cognitive-behavioralAntoni et al. (2012) Biological Psychiatry 71:366–372Laudenslager et al. (2016) Journal of Behavioral Medicine 39:346-54Antoni et al. (2016) Psychoneuroendocrinology in press

Mindfulness Bower et al. (2015) Cancer 121:1231-1240

YogaBower et al. (2014) Psychoneuroendocrinology 43:20-29

Tai ChiIrwin et al. (2014) Journal of the National Cancer Institute Monographs 2014:295-301

Cole, American Journal of Public Health 2013Cole, PLoS Genetics 2014

Mindfulness Creswell et al. (2012) Brain, Behavior, & Immunity 26:1095-1101

Relaxation response / mindfulnessBhasin et al. (2013) PLoS ONE 8:e62817

Yogic meditation Qu et al. (2013) PLoS ONE 8:e61910Black et al. (2013) Psychoneuroendocrinology 38:348-55

Molecular self-awareness

health care

epidemiology & policygenomic biofeedback

‐0.12

‐0.10

‐0.08

‐0.06

‐0.04

‐0.02

0.00

0.02

0.04

0.06

0.08

0.10

0.12

T1 T2

CTRA

gen

e compo

site (z‐score) World

OtherSelfControl

ReturnLyubomirsky et al., under review, 2016

Causal impact of prosocial behavior

http://www.newyorker.com/tech/elements/a‐better‐kind‐of‐happiness

Social isolation

Isolated

Control

3341532

High

Low

Time 1 Environment1 Body1RNA1

Behavior1


Behavior2


Behavior3

Recursive developmental remodeling

RNA = intra-organismic adaptation

Cole, Current Directions in Psychological Science 2009Cole, American Journal of Public Health 2013

Gray et al. Molecular Psychiatry 2014

social regulation of gene expression - stanford medicine · social regulation of gene expression...

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