Quantitative analysis of the developmental potential of cells and tissues based on evolutionary conservation of genes and regulatory regions

doi:10.3969/j.issn.1674-8115.2023.11.006

Abstract

Abstract:

Objective ·To study the relationship between evolution and the developmental process from the perspective of DNA sequence conservation, and explore their inherent principles. Methods ·First, conservation rate (CR) was established by analyzing the conservation of amino acid sequences of coding genes in 100 species to quantify the evolutionary conservation of genes. The relationship between CR and developmental potential was verified by using the feature genes involved in embryonic stem cells pathways. Secondly, cell type-specific genes and their characteristics in conservation were studied by analyzing the RNA sequencing (RNA-seq) data of the three early germ layers (ectoderm, mesoderm and endoderm) and their corresponding mature organs (brain, heart, liver, etc). Then, chromatin immunoprecipitation sequencing (ChIP-seq) data of enhancer histone H3 acetylated at lysine 27 (H3K27ac) from early germ layers and mature organs were collected to search for enhancer sites and identify super enhancers in various cells and tissues by using the ROSE procedure. Functional enrichment and signaling pathway analysis of genes was used to examine the identity correlation between SEs-regulated genes and the corresponding cell characteristics, to clarify whether the SEs identified in this study were consistent with the characteristics reported in previous studies. Finally, PhastCons program was used to calculate the DNA conservation score (CS) of non-coding regulatory regions to study their relationship with developmental potential. Results ·In the coding region of DNA, CR was successfully established to quantify the conservation of genes. The gene expression data of early germ layers and mature organs showed that the genes with higher conservation rate were more relevant to the stemness and early developmental process, and the differences between the tissues from early and late development could be distinguished by using CR. In the non-coding regions of DNA, it was found that the conservation of regulatory regions was also correlated with development. The CS of the SE sequences in the early developmental germ layers was significantly higher than that of the SE sequences in the corresponding mature organs. However, cell-specific typical enhancers (TEs) did not show such a trend. Conclusion ·During the developmental process, CR of genes expressed in the coding region decreases, and CS of super-enhancer DNA in the non-coding region decreases.

Key words: embryonic development, evolution, super enhancer, developmental genetics, conservation of DNA

CLC Number:

R394

WANG Zhiming, TONG Ran, YANG Chen, JIAO Huiyuan, WANG Yihao, LI Linying, WANG Yexin, ZHANG Feng, LI Lingjie. Quantitative analysis of the developmental potential of cells and tissues based on evolutionary conservation of genes and regulatory regions[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(11): 1384-1395.

Figures/Tables 12

TrendMD

References 20

1	ABZHANOV A. Von Baer′s law for the ages: lost and found principles of developmental evolution[J]. Trends Genet, 2013, 29(12): 712-722.
2	CARDOSO-MOREIRA M, HALBERT J, VALLOTON D, et al. Gene expression across mammalian organ development[J]. Nature, 2019, 571(7766): 505-509.
3	HOLLAND P W H, MARLÉTAZ F, MAESO I, et al. New genes from old: asymmetric divergence of gene duplicates and the evolution of development[J]. Philos Trans R Soc Lond B Biol Sci, 2017, 372(1713): 20150480.
4	LOWE C B, KELLIS M, SIEPEL A, et al. Three periods of regulatory innovation during vertebrate evolution[J]. Science, 2011, 333(6045): 1019-1024.
5	ONG C T, CORCES V G. Enhancer function: new insights into the regulation of tissue-specific gene expression[J]. Nat Rev Genet, 2011, 12(4): 283-293.
6	BULGER M, GROUDINE M. Functional and mechanistic diversity of distal transcription enhancers[J]. Cell, 2011, 144(3): 327-339.
7	SPITZ F, FURLONG E E M. Transcription factors: from enhancer binding to developmental control[J]. Nat Rev Genet, 2012, 13(9): 613-626.
8	WHYTE W A, ORLANDO D A, HNISZ D, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes[J]. Cell, 2013, 153(2): 307-319.
9	POTT S, LIEB J D. What are super-enhancers?[J]. Nat Genet, 2015, 47(1): 8-12.
10	WANG X, CAIRNS M J, YAN J. Super-enhancers in transcriptional regulation and genome organization[J]. Nucleic Acids Res, 2019, 47(22): 11481-11496.
11	KHAN A, ZHANG X G. dbSUPER: a database of super-enhancers in mouse and human genome[J]. Nucleic Acids Res, 2016, 44(D1): D164-D171.
12	LI Q L, LIN X, YU Y L, et al. Genome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers[J]. Nat Commun, 2021, 12(1): 6407.
13	YAMAGATA K, NAKAYAMADA S, TANAKA Y. Critical roles of super-enhancers in the pathogenesis of autoimmune diseases[J]. Inflamm Regen, 2020, 40: 16.
14	GONG J X, QIU C, HUANG D, et al. Integrative functional analysis of super enhancer SNPs for coronary artery disease[J]. J Hum Genet, 2018, 63(5): 627-638.
15	SUN W P, YAO S H, TANG J L, et al. Integrative analysis of super enhancer SNPs for type 2 diabetes[J]. PLoS One, 2018, 13(1): e0192105.
16	PÉREZ-RICO Y A, BOEVA V, MALLORY A C, et al. Comparative analyses of super-enhancers reveal conserved elements in vertebrate genomes[J]. Genome Res, 2017, 27(2): 259-268.
17	HEINZ S, BENNER C, SPANN N, et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities[J]. Mol Cell, 2010, 38(4): 576-589.
18	SRIVASTAVA M, SIMAKOV O, CHAPMAN J, et al. The Amphimedon queenslandica genome and the evolution of animal complexity[J]. Nature, 2010, 466(7307): 720-726.
19	VILLAR D, BERTHELOT C, ALDRIDGE S, et al. Enhancer evolution across 20 mammalian species[J]. Cell, 2015, 160(3): 554-566.
20	ZHANG J Q, ZHOU Y Q, YUE W, et al. Super-enhancers conserved within placental mammals maintain stem cell pluripotency[J]. Proc Natl Acad Sci USA, 2022, 119(40): e2204716119.

CR	Ectoderm development			Mesoderm development			Endoderm development
CR	Brain	Skin	Spinal cord	Heart	Skeletal muscle	Spleen	Liver	Lung	Pancreas
Progenitor-specific	0.72	0.72	0.73	0.72	0.74	0.75	0.71	0.74	0.75
Organ-specific	0.70	0.69	0.66	0.71	0.72	0.65	0.66	0.65	0.68
P value	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000
Fold change	1.02	1.05	1.10	1.02	1.02	1.16	1.08	1.14	1.11

CR	Ectoderm development			Mesoderm development			Endoderm development
CR	Brain	Skin	Spinal cord	Heart	Skeletal muscle	Spleen	Liver	Lung	Pancreas
Progenitor-specific	0.72	0.72	0.73	0.72	0.74	0.75	0.71	0.74	0.75
Organ-specific	0.70	0.69	0.66	0.71	0.72	0.65	0.66	0.65	0.68
P value	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000
Fold change	1.02	1.05	1.10	1.02	1.02	1.16	1.08	1.14	1.11

CS	Ectoderm development			Mesoderm development			Endoderm development
CS	Brain	Skin	Spinal cord	Heart	Skeletal muscle	Spleen	Liver	Lung	Pancreas
Progenitor-specific	0.15	0.15	0.14	0.15	0.15	0.15	0.18	0.18	0.18
Organ-specific	0.20	0.11	0.16	0.15	0.12	0.11	0.17	0.11	0.12
P value	0.000	0.000	0.000	0.614	0.001	0.000	0.000	0.000	0.000
Fold change	0.72	1.33	0.87	1.00	1.27	1.37	1.10	1.66	1.54

CS	Ectoderm development			Mesoderm development			Endoderm development
CS	Brain	Skin	Spinal cord	Heart	Skeletal muscle	Spleen	Liver	Lung	Pancreas
Progenitor-specific	0.15	0.15	0.14	0.15	0.15	0.15	0.18	0.18	0.18
Organ-specific	0.20	0.11	0.16	0.15	0.12	0.11	0.17	0.11	0.12
P value	0.000	0.000	0.000	0.614	0.001	0.000	0.000	0.000	0.000
Fold change	0.72	1.33	0.87	1.00	1.27	1.37	1.10	1.66	1.54

Tissue type	SE/n	SE element/n	TE/n
Ectoderm	839	5 078	74 570
Brain	825	5 654	50 322
Spinal cord	942	6 362	67 360
Skin	1 390	12 679	73 065
Mesoderm	508	4 054	79 411
Heart	1151	11 050	72 112
Spleen	1 712	15 581	78 865
Skeletal Muscle	1 496	12 534	80 847
Endoderm	671	3 770	57 547
Liver	777	3 424	43 749
Lung	538	4 304	57 040
Pancreas	1 657	16 475	94 829