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preterm birth is the leading cause of neonatal death worldwide with one million deaths directly resulting from premature birth .
more children under the age of 5 years die due to preterm birth than to aids , malaria , or tuberculosis
recently , the importance of epigenetics as a regulator of gene expression has become apparent and , potentially , epigenetic differences are driving gene expression leading to preterm birth .
epigenetics is the process by which interactions between genes and environment lead to stable changes in phenotype .
epigenetic changes ( e.g. , dna methylation , covalent histone modifications , etc . ) are by definition heritable , meaning that effects brought about by the environment at critical periods of development ( such as gestation ) can have long - term detrimental consequences . indeed , certain epigenetic changes are passed between generations which might explain some of the familial and intergenerational effects observed for preterm birth .
epigenetic information is conveyed via a synergistic interaction between mitotically heritable patterns of dna methylation and histone - mediated modifications to the chromatin structure . in mammals ,
dna methylation primarily involves the addition of methyl groups to cytosine residues present in a cpg dinucleotide .
hypermethylation of promoter regions of genes is typically associated with transcriptional repression whereas hypomethylation is usually permissive for gene activity .
histone modifications consist of a plethora of enzymatic modifications including acetylation , methylation , ubiquitination , and phosphorylation of different amino acids in the n terminal tails of histone proteins , the combination of which is thought to determine the local conformational state of the chromatin .
currently , over 60 different histone modifications have been identified although actual numbers are likely to be significantly higher .
recent work has clearly demonstrated that epigenetic marks determine time- ( temporal ) and tissue - specific ( spatial ) aspects of gene expression throughout development .
in contrast , others might carry an epigenetic signature that is less sensitive to the normal stimuli of labour , therefore , leading to dysfunctional labour or postdates delivery .
the environment presumably plays a crucial role in bringing about these epigenetic changes that are critical for the safe passage of gestation and later outcomes .
an increasing number of diverse factors are now known to epigenetically regulate genes , including age , inflammation , gender , genotype , stress , nutrition , metabolism , drugs , and infection , thus heightening the relevance of the study of the epigenetics of preterm birth .
both classes of epigenetic modification ( e.g. , dna methylation and covalent histone modifications ) can be reversed through treatment with a chemical inhibitor : 2-deoxy-5-azacytidine ( aza ) that inhibits dna methylation leading to global hypomethylation of dna , while treatment with an inhibitor of histone deacetylation such as trichostatin a ( tsa ) leads to increased levels of histone acetylation . in both cases
we demonstrated in an earlier study   that the combination treatment of human choriodecidual explants with aza and tsa leads to a massive increase in il-1 production in response to lps . in the present study
lipopolysaccharide ( lps ) , 5-aza-2-deoxycytidine ( aza ) , and trichostatin a ( tsa ) were purchased from sigma chemical ( st . louis , mo ) .
culture media and fetal calf serum ( fbs ) were from life technologies ( carlsbad , ca , usa ) .
human il1 , tnf , il10 , and il1ra elisa kits were purchased from bd bio sciences .
placental tissues were collected from women undergoing elective caesarean section at term , with the approval of the northernx regional ethics committee .
three individual placentae from singleton pregnancies of healthy nonsmoking mothers were used in the study . in triplicate , villous and amnion tissues
explants were cultured in 12-well plates ( three pieces of tissue to a well ) in dmem / f12 media supplemented with glutamax , 10% fbs , and 1% antibiotic - antimycotic and incubated at 37c in humid 5% co2/95% air for 24  h ( modified from [ 18 , 19 ] ) .
explant treatments included the use of 5-aza-2-deoxycytidine ( aza ) , which inhibits dna methylation , and/or trichostatin a ( tsa ) which inhibits histone deacetylation .
doses and times were chosen to be consistent with published literature [ 18 , 20 ] .
24 hours following placental dissection , the media were replaced with serum - free media ( dmem / f12 with glutamax and 0.1% bovine gamma globulin and 1% antibiotic - antimycotic medium ) .
explants were treated with either 200  nm aza alone , tsa ( 300  nm ) alone , 5  m aza with tsa ( 300  nm ) , or the dmso carrier and cultured for 48  h , with media refreshed once during this time .
this represented a 48  h preincubation  aza ( the action of aza is passive and requires cell division for action ) .
the treatment period commenced 72  h postdissection and consisted of the addition of 300  nm tsa or dmso carrier in fresh media , in the presence or absence of lps ( 5  g / ml ) , to the explants for a duration of 24  h. the media were collected following the treatment and the wet weight of the tissue in each well determined so that cytokine production rates could be normalized .
measurements of pro- ( il1 , tnf ) and anti - inflammatory ( il10 , il1ra ) cytokines were conducted on cultured media using elisas according to manufacturers ' specifications .
production rates of cytokines were calculated as picograms per gram wet tissue weight per 24  h and are presented as % basal control values ( means    se , n = 3 ) .
statistical significance was determined by anova , and p < 0.05 was considered to be significant .
lps treatment significantly ( p < 0.05 ) increased the production of il-1 ( ~1034-fold ) , tnf ( ~23>100-fold ) and il10 ( ~610-fold ) after 24  h of treatment in villous explants , as expected .
aza treatment did not have any significant effect on any cytokines ' production tested either alone or in combination with lps .
interestingly , however , the stimulatory effects of lps on tnf production were partially mitigated ( p < 0.05 ) by tsa treatment in villous explants .
neither lps nor the tsa or aza had any significant effect on the cytokine production in amnion explants after 24  h of treatment .
conceivably , epigenetic modifications ( e.g. , dna methylation and covalent histone modifications ) might render individuals more or less susceptible to either term or preterm birth by modulating the expression of genes that are effectors of the parturition pathway , for example , the contraction - associated proteins , cox-2 , oxytocin , and prostaglandin receptors in myometrium .
thus , some individuals may have a sensitive epigenetic phenotype that leads to an increased susceptibility to preterm labour .
global dna methylation is increased in preterm preeclamptic placentae . in this study , in conjunction with our previous work   we have shown that epigenetic regulation of cytokine production is tissue specific in gestational tissues .
aza / tsa treatment resulted in a massive increase in il-1 production in response to lps whereas in amnion and villous placenta this did not occur although a small positive trend in mean production was noted ( figures 1 and 2 ) .
this raises the question of tsa - like moieties being developed to attenuate inflammatory process in the human placenta .
the disadvantage of such an approach is , of course , the enhancement of il-1 production in choriodecidua by such an agent .
the tissue - specific nature of these regulatory mechanisms means that we must be cautious in our approach to such matters .
amnion clearly does not respond to the inflammatory challenge of lps although it remains a significant source of cytokine production and once activated can respond vigorously to modifications of the cytokine environment [ 2225 ] .
villous placenta seems crudely to be more active in proinflammatory cytokine biosynthesis than anti - inflammatory cytokine biosynthesis .
this is clearly dangerous for the fetus and may play a role in the fetal inflammatory syndrome , although clearly direct evidence must be obtained before conclusions are drawn .
furthermore , treatment with a histone deacetylation inhibitor can partially abrogate lps - stimulated tnf production in villous placenta but not amnion .
the mechanisms of human preterm labour appear inextricably linked to cytokine biosynthesis by gestational tissues . in turn , cytokine production by gestational tissues has been shown to be regulated by epigenetic mechanisms . in this paper , we demonstrate that cytokine production in gestational tissues is regulated epigenetically in a tissue - specific manner . 
 furthermore , we show that treatment with a histone deacetylation inhibitor can partially abrogate lps - stimulated tnf production in villous placenta but not amnion . 
 lps treatment significantly ( p < 0.05 ) increased the production of il-1 ( 1034-fold ) , tnf ( 23>100-fold ) and il10 ( 610-fold ) after 24  h of treatment in villous explants , as expected . 
 there were no significant lps effects on il1ra production . 
 aza treatment did not have any significant effect on any cytokines ' production tested either alone or in combination with lps . 
 interestingly , however , the stimulatory effects of lps on tnf production were partially mitigated ( p < 0.05 ) by tsa treatment in villous explants . 
 we suggest caution in the consideration of histone deacetylation inhibitors in pregnancy due to the different responses in gestational tissues .