TABLE 2.
Wide search for genes correlated to the proliferative activation of stem cells: selection of the 866 differentially expressed GLM genes whose expression was significantly changed in the dentate gyrus by running in both Set A and Set E (termed Set A_Set E_GLM). This analysis is parallel to, but wider than, the one shown for Set D_Set E_GLM in Table 1. In fact the 866 genes identified by the GLM procedure, i.e., whose expression was significantly changed by the interaction between running and genotype, were further selected for genes changed by running with p < 0.05 in both pairwise comparisons of Set A (p16 KO RUN vs p16 KO CTL) and of Set E (p16 KO RUN vs p16 WT RUN). The total number of genes identified in this way was 106: this group was named Set A_Set E_GLM selection and its differential gene regulation reproduces the pattern of proliferative activation of p16 KO stem cells by running, with respect to the other groups. Moreover, Set A_Set E_GLM selection includes all genes of Set D_Set E_GLM shown in Table 1, indicating that the Set A_Set E_GLM is more comprehensive. The list shown here is a selection among the Set A_Set E_GLM genes of those that could be functionally correlated, according to the existing literature, to the activation of stem and progenitor cells of the dentate gyrus, sorted by decreasing log2 fold change in Set A. The full list of 106 genes of Set D_Set E_GLM is shown in Supplementary Table S6. The genes highlighted in red are those with significant differential expression also in Set B (p16 KO CTL vs p16 WT CTL groups), i.e., the set representing the genetic signature of p16 knockout. p-values for Set A and Set E genes were obtained by DESeq2 analysis through the Wald test, while p-values for genes selected by the GLM model were obtained by testing the difference between the ‘full’ and ‘reduced’ model (Love et al., 2014).
| Set A | Set E | GLM | |||||
|---|---|---|---|---|---|---|---|
| KO RUN vs KO CTL | KO RUN vs WT RUN | ||||||
| Gene name | log2Fold change | P-value | log2Fold change | P-value | P-value | Gene function correlated to stem cell activation | References |
| Tfap2c | 2.5099 | 0.0041173 | 2.1996 | 0.022623 | 0.0017784 | Promotes hippocampal neurogenesis | Mateus-Pinheiro et al. (2017) |
| Npw | 1.8813 | 0.0005558 | 1.0357 | 0.043069 | 0.043133 | Hippocampal signaling | Chottova Dvorakova (2018) |
| Nlrc5 | 1.7969 | 0.0000344 | 0.91737 | 0.045703 | 0.0014689 | Negative ROS regulator | Li et al. (2021a) |
| Mki67 | 1.5041 | 0.0000001 | 1.487 | 2.12E-05 | 0.00055784 | Cell cycle regulator | Scholzen and Gerdes (2000) |
| Lepr | 1.4658 | 0.0000007 | 0.80141 | 0.001078 | 0.0041875 | Synaptic plasticity regulator | Dhar et al. (2014) |
| Clcn1 | 1.3064 | 0.0079431 | 0.74279 | 0.0053492 | 0.0098998 | Synaptic regulator | Imbrici et al. (2015) |
| Cyp11a1 | 1.1998 | 0.0001284 | 0.54095 | 0.023468 | 0.010046 | Hippocampus response to injury | Chia et al. (2008) |
| Top2a | 1.1833 | 0.00011062 | 1.4402 | 2.84E-05 | 0.0081051 | Cell cycle regulator | Gómez-Herreros et al. (2014) |
| Eomes | 1.1415 | 0.008134 | 2.38 | 1.88E-05 | 0.00023908 | Hippocampal progenitor cell marker | Nelson et al. (2020) |
| Zic4 | 1.099 | 0.01369 | 0.91747 | 0.042865 | 0.04725 | Activator of stem cell proliferation | Blank et al. (2011) |
| Pole | 1.0115 | 0.0000071 | 0.34811 | 0.039086 | 0.011691 | Cell cycle regulator | Hogg and Johansson (2012) |
| Insm2 | 0.99643 | 0.0470330 | 1.1039 | 0.044601 | 0.02797 | Glycolitic pathway activator | Wang et al. (2018) |
| Mocos | 0.94776 | 0.0000387 | 0.3783 | 0.020257 | 0.015645 | Negative ROS regulator | Féron et al. (2016) |
| Unc13d | 0.89326 | 0.0000370 | 0.46491 | 0.024812 | 0.025937 | Synaptic plasticity regulator | Dittman (2019) |
| Slc18a2 | 0.88805 | 0.0012173 | 0.86778 | 0.0011748 | 0.016933 | Synaptic plasticity regulator | Stefanovic et al. (2016) |
| Prc1 | 0.87277 | 0.01267 | 1.1565 | 0.0027045 | 0.0083644 | Cell cycle regulator | Mollinari et al. (2002) |
| Cenpf | 0.82583 | 0.00035633 | 0.8323 | 0.00013571 | 0.0014211 | Synaptic plasticity regulator | Tanaka et al. (2012) |
| Gstm2 | 0.77843 | 0.0048713 | 0.81297 | 0.0047004 | 0.021936 | Negative ROS regulator | Segura-Aguilar et al. (2014) |
| Dpf3 | 0.44617 | 0.000012 | 0.28425 | 0.0014714 | 0.0006557 | Promotes stem cell proliferation | Lessard et al. (2007) |
| Trp73 | 0.41055 | 0.04942 | 0.31332 | 0.027558 | 0.018847 | Promotes stem cell proliferation | Talos et al. (2010) |
| Ncapd2 | 0.38713 | 0.0001085 | 0.16293 | 0.04469 | 0.023229 | Promotes cell proliferation | He et al. (2023) |
| Lpin2 | 0.37591 | 8.83E-11 | 0.17873 | 0.015751 | 0.00075486 | Fatty acid metabolism regulator | Chen et al. (2015) |
| Dbn1 | 0.37119 | 0.000000031 | 0.14431 | 0.010052 | 0.0081834 | Synaptic plasticity regulator | Jung et al. (2015), Aoki et al. (2005) |
| Grm1 | 0.30756 | 0.00023736 | 0.20714 | 0.0025639 | 0.0018544 | Synaptic plasticity regulator | Baskys et al. (2005) |
| Cog1 | 0.26607 | 0.00024705 | 0.099728 | 0.047439 | 0.0038386 | Regulator of neuronal vesicles | Climer et al. (2018) |
| Zfp143 | 0.26463 | 0.0049829 | 0.18189 | 0.043793 | 0.0011626 | Regulator of stemness | Choi et al. (2012) |
| Gabbr2 | 0.22451 | 0.000032 | 0.13118 | 0.024323 | 0.0091136 | Synaptic plasticity regulator | Heaney and Kinney (2016) |
| Glrb | −0.14419 | 0.036066 | −0.14323 | 0.0083886 | 0.0010861 | Synaptic plasticity regulator | Lee et al. (2017) |
| Cnbp | −0.22151 | 0.0021957 | −0.14838 | 0.0061765 | 0.031318 | Proliferation regulator | Calcaterra et al. (2010) |
| Nrxn1 | −0.23221 | 0.00000080 | −0.10842 | 0.013282 | 0.013987 | Synaptic plasticity regulator | Luo et al. (2021) |
| Mzt1 | −0.2335 | 0.00020106 | −0.15501 | 0.014654 | 2.71E-06 | Cell division regulator | Batzenschlager et al. (2014) |
| Purb | −0.24099 | 0.00065256 | −0.1747 | 0.00039673 | 2.41E-05 | Exercise-dependent synaptic plasticity regulator | Chen et al. (2007) |
| Fgf12 | −0.25472 | 0.00087818 | −0.15989 | 0.01975 | 0.032654 | Synaptic plasticity regulator | Zhang et al. (2012) |
| Pbx1 | −0.26346 | 0.0000677 | −0.1229 | 0.016314 | 0.043764 | Stem cell regulator | Hau et al. (2021) |
| Nudt3 | −0.28487 | 0.0015394 | −0.17299 | 0.032189 | 0.013985 | Involved in insulin signaling | Williams et al. (2015) |
| Pou3f3 | −0.31284 | 0.0000008 | −0.17004 | 0.038589 | 0.00028684 | Stem cell regulator; favors quiescence | Castro et al. (2006) |
| Galk1 | −0.34371 | 0.0032957 | −0.26377 | 0.041561 | 0.0028659 | Glycolysis regulator | Oh et al. (2020) |
| Crim1 | −0.3589 | 0.0016505 | −0.24056 | 0.013359 | 0.00066872 | Involved in neural development | Ponferrada et al. (2012) |
| Rgs14 | −0.38356 | 0.0000044 | −0.22733 | 0.0043943 | 8.33E-05 | Synaptic plasticity negative regulator | Evans et al. (2018) |
| Grm3 | −0.50434 | 0.00086289 | −0.15248 | 0.045464 | 0.020496 | Synaptic plasticity regulator, Neurotransmitter receptor | Dogra et al. (2021) |
| Ttc9 | −0.5047 | 0.0000805 | −0.33005 | 0.01287 | 0.002817 | Cell migration ? | Cao et al. (2008) |
| Klhl4 | −0.50857 | 0.0017137 | −0.31945 | 0.02117 | 0.0069358 | Cell cycle regulator | Choi et al. (2020) |
| Gabra3 | −0.595 | 0.0017071 | −0.2893 | 0.041659 | 0.015167 | Synaptic plasticity regulator, Neurotransmitter receptor | Wagner et al. (2021) |
| Ramp3 | −0.75442 | 0.0010749 | −0.60432 | 0.018916 | 0.015335 | Pro-differentiative | Li et al. (2021b) |
| Sp8 | −1.0514 | 0.0048701 | −0.88825 | 0.022895 | 0.012781 | Marker of quiescent stem cells | Zhang et al. (2016) |
| Chrm5 | −1.3817 | 0.010806 | −1.0349 | 0.025201 | 0.026236 | Synaptic plasticity regulator, Neurotransmitter receptor | Sakata and Overacre (2017) |
| Nov | −1.6364 | 0.034359 | −0.85695 | 0.0011469 | 0.016149 | Inhibitor of progenitor cell proliferation | Le Dréau et al. (2010) |