Evolution of DNAase I Hypersensitive Sites in MHC Regulatory Regions of Primates

Jin, Yabin; Gittelman, Rachel M.; Lu, Yueer; Liu, Xiaohui; Li, Ming D.; Ling, Fei; Akey, Joshua M.

doi:10.1534/genetics.118.301028

Cited by 10 publications

(7 citation statements)

References 30 publications

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“…In further research, it would be interesting to extend this single-cell approach that revealed a higher percentage of decondensed MHC alleles in activated macrophages by performing DNAse1 hypersensibility assay which allows targeting the regions of chromatin that have lost their compact structure. This kind of approach has been performed to map the DNAse 1 hypersensitive regions in the MHC of Primates to determine the disease-causing variants for most major histocompatibility complex (MHC)-associated diseases [ 48 ]. Similarly, as we detected a strong overexpression of TNFα in human and porcine macrophages following LPS/IFNγ activation, a comparative study of its epigenetic profile [ 49 ] (both at the DNA methylation and histone marks levels) in resting and activated cells would further our results.…”

Section: Discussionmentioning

confidence: 99%

The 3D nuclear conformation of the major histocompatibility complex changes upon cell activation both in porcine and human macrophages

Mompart

Kamgoué

Lahbib-Mansais

et al. 2021

BMC Mol and Cell Biol

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Background The crucial role of the major histocompatibility complex (MHC) for the immune response to infectious diseases is well-known, but no information is available on the 3D nuclear organization of this gene-dense region in immune cells, whereas nuclear architecture is known to play an essential role on genome function regulation. We analyzed the spatial arrangement of the three MHC regions (class I, III and II) in macrophages using 3D-FISH. Since this complex presents major differences in humans and pigs with, notably, the presence of the centromere between class III and class II regions in pigs, the analysis was implemented in both species to determine the impact of this organization on the 3D conformation of the MHC. The expression level of the three genes selected to represent each MHC region was assessed by quantitative real-time PCR. Resting and lipopolysaccharide (LPS)-activated states were investigated to ascertain whether a response to a pathogen modifies their expression level and their 3D organization. Results While the three MHC regions occupy an intermediate radial position in porcine macrophages, the class I region was clearly more peripheral in humans. The BAC center-to-center distances allowed us to propose a 3D nuclear organization of the MHC in each species. LPS/IFNγ activation induces a significant decompaction of the chromatin between class I and class III regions in pigs and between class I and class II regions in humans. We detected a strong overexpression of TNFα (class III region) in both species. Moreover, a single nucleus analysis revealed that the two alleles can have either the same or a different compaction pattern. In addition, macrophage activation leads to an increase in alleles that present a decompacted pattern in humans and pigs. Conclusions The data presented demonstrate that: (i) the MHC harbors a different 3D organization in humans and pigs; (ii) LPS/IFNγ activation induces chromatin decompaction, but it is not the same area affected in the two species. These findings were supported by the application of an original computation method based on the geometrical distribution of the three target genes. Finally, the position of the centromere inside the swine MHC could influence chromatin reorganization during the activation process.

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Section: Discussionmentioning

confidence: 99%

The 3D nuclear conformation of the major histocompatibility complex changes upon cell activation both in porcine and human macrophages

Mompart

Kamgoué

Lahbib-Mansais

et al. 2021

BMC Mol and Cell Biol

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“…Genetically, viruses appear to have driven ~30% of all adaptive amino acid changes in the part of the human proteome conserved within mammals (Enard et al, 2016). There is human‐chimpanzee divergence in regulatory sequences related to immune genes (He et al, 2016; Jin et al, 2018), including in microglia (brain immune cells, Xu et al, 2018), and there are human‐specific coding genes related to immunity (Costantini et al, 2019), including one expressed in microglia (Hayakawa et al, 2005). Because positive selection on immune‐related genes is common in primates (van der Lee et al, 2017), divergent evolution of immune genes could simply be due to Red Queen dynamics.…”

Section: Physiological and Genetic Evidence For Human‐specific Immune...mentioning

confidence: 99%

Homo medicus: The transition to meat eating increased pathogen pressure and the use of pharmacological plants in Homo

Hagen

Blackwell

Lightner

et al. 2023

American Journal of Biological Anthropology

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The human lineage transitioned to a more carnivorous niche 2.6 mya and evolved a large body size and slower life history, which likely increased zoonotic pathogen pressure. Evidence for this increase includes increased zoonotic infections in modern hunter‐gatherers and bushmeat hunters, exceptionally low stomach pH compared to other primates, and divergence in immune‐related genes. These all point to change, and probably intensification, in the infectious disease environment of Homo compared to earlier hominins and other apes. At the same time, the brain, an organ in which immune responses are constrained, began to triple in size. We propose that the combination of increased zoonotic pathogen pressure and the challenges of defending a large brain and body from pathogens in a long‐lived mammal, selected for intensification of the plant‐based self‐medication strategies already in place in apes and other primates. In support, there is evidence of medicinal plant use by hominins in the middle Paleolithic, and all cultures today have sophisticated, plant‐based medical systems, add spices to food, and regularly consume psychoactive plant substances that are harmful to helminths and other pathogens. We propose that the computational challenges of discovering effective plant‐based treatments, the consequent ability to consume more energy‐rich animal foods, and the reduced reliance on energetically‐costly immune responses helped select for increased cognitive abilities and unique exchange relationships in Homo. In the story of human evolution, which has long emphasized hunting skills, medical skills had an equal role to play.

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“…In addition to functionally annotating HARs, epigenetic data have been used to study the evolution of human gene regulation in two other ways. First, candidate regulatory elements can be generated from human data and subsequently analyzed for human variants and positive selection (15,23,31,32). A substantial minority of the resulting elements overlap previously identified HARs, but many new fast-evolving enhancers have been discovered with this strategy.…”

Section: Harsmentioning

confidence: 99%

Enhancer Function and Evolutionary Roles of Human Accelerated Regions

Whalen

Pollard

2022

Annu. Rev. Genet.

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Human accelerated regions (HARs) are the fastest-evolving sequences in the human genome. When HARs were discovered in 2006, their function was mysterious due to scant annotation of the noncoding genome. Diverse technologies, from transgenic animals to machine learning, have consistently shown that HARs function as gene regulatory enhancers with significant enrichment in neurodevelopment. It is now possible to quantitatively measure the enhancer activity of thousands of HARs in parallel and model how each nucleotide contributes to gene expression. These strategies have revealed that many human HAR sequences function differently than their chimpanzee orthologs, though individual nucleotide changes in the same HAR may have opposite effects, consistent with compensatory substitutions. To fully evaluate the role of HARs in human evolution, it will be necessary to experimentally and computationally dissect them across more cell types and developmental stages. Expected final online publication date for the Annual Review of Genetics, Volume 56 is November 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Evolution of DNAase I Hypersensitive Sites in MHC Regulatory Regions of Primates

Cited by 10 publications

References 30 publications

The 3D nuclear conformation of the major histocompatibility complex changes upon cell activation both in porcine and human macrophages

The 3D nuclear conformation of the major histocompatibility complex changes upon cell activation both in porcine and human macrophages

Homo medicus: The transition to meat eating increased pathogen pressure and the use of pharmacological plants in Homo

Enhancer Function and Evolutionary Roles of Human Accelerated Regions

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