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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Developmental biology - Gene Methylation

Gene Regulation, Digital and Random?

If the genome is computer hardware, the epigenome is the software that turns genes off and on...

Every cell in our body has the same set of genes, our genome, and can potentially become any type of cell. During development, the epigenome governs the process leading a cell to become either a skin cell or a neuron or any other cell type. If the genome, meaning all the genetic material in a body, is like computer hardware, then the epigenome - all external affects on those genes, is the software that turns certain genes on and others off, based on external conditions such as ambient temperature and humidity.


Diagram of DNA strand representing specific gene area made "abnormal" by methyl group attachments.

The epigenome is encoded by a set of specific chemical modifications called DNA methylations. In this study published in the journal Science, researchers from the National Institutes of Health Roadmap Epigenomics Project note how DNA methylation groups can randomly attach turning on or off gene expression for a fraction of time.

A cell mechanism called Sequence-Dependent or Allele-Specific Methylation (SD-ASM), uses whole-genome bisulfite sequencing (WGBS) to allow us to see gene regulation at single-molecule resolution in a multitude of human cell types. Therefore, we were able to determine epigenomic differences in the paternal and maternal chromosomes of the same gene existing in individual cells, explains Aleksandar Milosavljevic PhD, professor of molecular and human genetics, and co-director of computational and integrative biomedical research at Baylor College of Medicine in Houston, Texas, USA.
Using this high-resolution approach, Milosavljevic and colleagues discovered that the SD-ASM mediated gene works like a house thermostat. A house thermostat has a preset temp at which the air conditioning (AC) will turn on when the house air is above that temp. The process is digitally regulated, the AC machine is either on to cool the interior temp, or off. There is no intermediate level.

Like a thermostat, gene regulation is also digital. However, a gene is either on or off for a fraction of the time - again with no intermediate levels.

"We also discovered the process of gene regulation is stochastic [random]," said Milosavljevic, also a member of Baylor College of Medicine, at the Dan L Duncan Comprehensive Cancer Center. "Returning to the thermostat analogy, the probability of the AC turning on when the temperature reaches a preset value of 74 degrees is 100 percent. In a stochastic thermostat, the probability of the AC machine turning on increases as the temperature reaches 74 degrees, but it is not 100 percent 'determined to occur' when that temperature is reached. There is still a chance that the AC will not turn on at 74 degrees, but the probability of the AC turning on is higher as the temperature rises."

In the case of the gene regulation mechanism, specific genetic variants that control the paternal and maternal genes may represent different 'preset temperature values' in the thermostat analogy, causing differences in the degree to which maternal or paternal genes are expressed in each human cell.

"For example, for a particular gene in a neuron, the maternal genetic 'thermostat' may be set to 'turn on the gene at 73 degrees', and the paternal gene at 74 degrees. That means that the paternal and maternal genes are turned on differently which creates an imbalance between the two copies of that gene," according to Milosavljevic. "We found that between 5 and 8 percent of the epigenome shows this type of imbalance." Implications of this finding extends to a number of biomedical fields.

"For instance, our findings may add another layer of complexity - so far not taken into account in certain intricate human diseases. If we add this layer of complexity, we might be able to better understand how dosage-sensitive genes may contribute to human diseases that have so far been hard to tackle, such as neuropsychiatric disorders,"according to Milosavljevic. "This work is meant to provide important insight into a new layer of biological complexity, hopefully creating the basis for subsequent research in specific diseases."

To assess the impact of genetic variation in regulatory loci on human health, we construct a high-resolution map of allelic imbalances in DNA methylation, histone marks, and gene transcription in 71 epigenomes from 36 distinct cell and tissue types from 13 donors. Deep whole-genome bisulfite sequencing of 49 methylomes reveals sequence-dependent CpG methylation imbalances at thousands of heterozygous regulatory loci. Such loci are enriched for stochastic switching, defined as random transitions between fully methylated and unmethylated states of DNA. The methylation imbalances at thousands of loci are explainable by different relative frequencies of the methylated and unmethylated states for the two alleles. Further analyses provide a unifying model that links sequence-dependent allelic imbalances of the epigenome, stochastic switching at gene regulatory loci, and disease-associated genetic variation.

Authors: Vitor Onuchic, Eugene Lurie, Ivenise Carrero, Piotr Pawliczek, Ronak Y. Patel1, Joel Rozowsky, Timur Galeev5, Zhuoyi Huang1, Robert C. Altshuler, Zhizhuo Zhang, R. Alan Harris, Cristian Coarfa, Lillian Ashmore, Jessica W. Bertol, Walid D. Fakhouri, Fuli Yu, Manolis Kellis, Mark Gerstein, Aleksandar Milosavljevic.

The authors declare no competing financial interests.

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Aug 27, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

This diagram represents how DNA is compressed by wrapping around histone methylation molecules to fit compactly within a cell nucleus. Epigenetics most often denotes changes from this compression that affect gene function. When DNA is loosely wrapped around histone it functions or is "expressed". Repressor proteins can also attach to silence regions of the DNA strand.

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