for example, what signal and when say to lysine methyl transferase for addition of methyl group (one or two or three?) to histone tail for making an epigenetic or histone code? what mechanism control that? and what mechanism control that mechanism?
This regulation is complex and multi-aspect. Histone codes and DNA methylation codes work together and they have interactions with cellular signaling pathways and nuclear transcription regulators. Some of signaling pathways such as MAPK regulate chromatin remodeling complexes activities. These complexes target sites for modification via interaction with other proteins (Transcription factors, hormon receptors & ..) and some non-coding RNAs (such as HOTAIR lncRNA).On the other hand DNA methyltransferases interacts with histone modifications enzymes. Also there are interactions between histone tails inter- and intra- nucleosomes. So you can see there is regulation network that every element in this has interaction with others.
Histone methylation patterns are imprinted during development, as pluripotency becomes more restricted and cell lineages are specified. We know much about the methyltransferases of the Trithorax Group (MLLs in mammals) and the Polycomb Group (Ezh1, 2) and their co-factors, but how they recognize specific genes at specific times in development is still unclear. I think many developmental DNA binding proteins such as Hox, Pax, Fox, Sox etc. are likely to provide the tissue and gene specificity for epigenetic modifications. Whether histone acetylation is truly an epigenetic mark is debatable, as this correlates with transcription and is rapidly turned over by HDACs. I would disagree with the above comment. Signaling effectors downstream of MAPKs (erk, elk, p38) and other common pathways (WNTs, FgFs, Bmps, Gli,) function to regulate target genes that are accessible on the epigenome but do not alter the epigenome by changing the epigenetic histone methylation imprints. This explains how different cell types can respond to the same input with different target gene activation.
Thank you Dr. Dressler for your accurate comment. I mean signaling pathways affect chromatin remodeling complexes activities, for example HAT phosphorylation through MAPK pathway enhances its activity. These pathways linked extra cellular signals to chromatin modifications through this way. Many extra cellular signals affect on cell development and functions, especially in neurons. So epigenetic developmental marking and environmental responses regulations in part is under signaling pathways effects. Chromatin remodeling complexes target sites for modification (as you said specificity for time and place of epigenetic modifications) with regulators proteins (transcription factors , hormon receptors & .. that certainly have DNA binding domain as you mentioned) and ncRNAs (such as Long non-coding RNAs in-cis and -trans routing these complexes to specific target sites). However I think there are some extra cellular signals that affect chromatin modifications through signaling pathways, hormone receptors & .. (regulators that transport extra cellular signals to DNA bound proteins & or DNA) and internal signals such as DNA breaks ,DNA topology changes & .. which regulate chromatin modification status.
To my knowledge, before the cells enter totipotent stage, their entire epigenetic marks are removed.This stage of the cell is called blank. However, for a very short period of time the genes that are going to be silenced by methylation in later stages are getting mathylated and demethylated to mark the genes for future methylation. Even for X chromosome silencing that is one of the pathways to determine which chromosome is going to be silenced. . Further the histone modification patterns and DNA methylation determine the fate of the cells.
However, there are certain epigenetic marks that are the consequence of parental environment. In this case, the parental generation phenotypes are altered as a plastic response to environmental cue. This happens when certain genes are required to be on or off in-order to respond to a new condition which was beyond the previous experiences of the individual. In this case, the same modifications are copied on the germ-line and the acquired phenotype can pass to the progenies since the these modification can skip being removed in the blank stage through self sustaining feedback loops. This determines the specific modifications on specific sites.
However, I didnt know that histone acetylation is debated as an epigenetic modification. Professor Dresseler, I will be grateful if you can explain this abit. Histone acetylation is a non-genetic modification that can pass to the subsequent generations. What is the difference between histone acetylation as a modification with for example histone methylation?
Parisa, you hit the nail on the head as we say in the US. Histone acetylation is a modification, but it is NOT passed on to subsequent generations. Studies in yeast show histone acetylation has a half-life of minutes. Acetylation and deacetylation are very dynamic. Yes, histone acetylation correlates with gene expression and is likely to reduce the affinity of nucleosomes to DNA, thus enabling sliding or movement of nucleosomes so that transcription and DNA replication are facilitated. Histone acetylation is required for gene expression but that dos not make it a heritable epigenetic mark on chromatin in the way that DNA methylation or histone methylation can be.
Last but not least, epigenetic modifiers were first identified in genetic screens in flies. These were unbiased and found families of genes that generally fell into the Polycomb and Trithorax group. We now know that Polycomb and Trithorax genes encode histone methyltransferases and their co-factors. However, not a single histone acetylase or deacetylase was found in unbiased screens for epigenetic modifiers.
thank you Mina and Gregory for your attention.
as you know there are different modification on histone tail that less understood about their role on DNA and histone behavior and there are multiple reader domains for interpreting them. see this please:
S.B. Rothbart, B.D. Strahl, Interpreting the language of histone and DNA modifications, Biochim. Biophys. Acta (2014),
and i think that i have to study more for my lecture, so i need the papers and references about how control of histone writers for adding a specific mark at specific site and time.
anybody can help me?
thanx
Dear Professor Dresser,
Many thanks for your kind response.
However, in my experiment I found that an environmental insult in the parental generation (clonal population of brine shrimp) can readily modify the global H3 and H4 acetylation for 3 subsequent non-treated generations. The mark was very fluctuating for DNA methylation as it seems that the body was trying to figure out the wild type methylation in absence of the treatment.
Is there any difference in including Histone acetylation as an epigenetic mark or transgenerational epigenetic mark?
Is there any differentiation between acquired acetylation and wild type acetylation?
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