The NRF transcription factors NRF1, NRF2, and NRF3, are a subset of Cap‘n’collar transcriptional regulators which modulate the expression of genes harboring antioxidant-response element (ARE) sequences within their genomic loci. Despite the emerging physiological importance of NRF family members, the repertoire of their genetic targets remains incompletely defined. Here we use RNA-sequencing-based transcriptional profiling and quantitative proteomics to delineate the overlapping and differential genetic programs effected by the three NRF transcription factors. We then create consensus target gene sets regulated by NRF1, NRF2, and NRF3 and define the integrity of these gene sets for probing NRF activity in mammalian cell culture and human tissues. Together, our data provide a quantitative assessment of how NRF family members sculpt proteomes and transcriptomes, providing a framework to understand the critical physiological importance of NRF transcription factors and to establish pharmacologic approaches for therapeutically activating these transcriptional programs in disease.

Despite lower Hb concentration, Tibetans resident at 4200m exhibit greater exercise capacity than do Han Chinese also resident at 4200m. Whether these adaptations are maintained at intermediate altitude and/or acute hypobaric hypoxia are unknown. Thirty‐seven healthy, non‐smoking subjects, all resident for at least six months at ~2200 m, of Tibetan (N _Male = 10; N _Female = 9) or Han Chinese (N _Male = 8; N _Female = 10) ancestries were studied at 2200 m and then during acutely simulated altitude (4200 m in a hypobaric chamber). Subjects performed an incremental cycle test to exhaustion. At peak exercise, oxygen consumption (VO2max), cardiac output (QTmax), ventilation (VE), hemoglobin ([Hb]), blood oxygen saturation (SaO2), and arterial blood gases were measured and diffusing capacity in lung (DL) and muscle (DM) were calculated. At peak exercise at 2200 m, Tibetan males had 1.23 g/dL less [Hb] compared to their Han Chinese male counterparts (p = 0.03). Tibetan females had 1.05 g/dL less [Hb] then Han Chinese females, but the result is not statistically significant (p = 0.064) Compared to Han Chinese, Tibetan females tended to have 4.85 and 2.72 mLmin ⁻¹ Kg ⁻¹ higher VO2max at 2200 m and 4200 m (both p = 0.03). For males, Tibetans tended to have 6.90 and 2.78 mLmin ⁻¹ Kg ⁻¹ higher VO2max than Han Chinese. However, the difference in VO2max was not significant in males at 2200 m or 4200 m (p = 0.095, p = 0.306, respectively). Tibetan males, but not females, had a significantly higher lung O2 diffusing capacity (DL) compared to Han Chinese (p = 0.028 for males; p = 0.192 for females). Tibetans also tended to have increased muscle O2 diffusing capacity (DM), but the difference was not statistically significant. Tibetan compared to Han Chinese females exhibited higher VE during maximal exercise at both 2200 m and 4200 m (p < 0.03, p < 0.02, respectively). The differences were not significant in males (p > 0.54 for 2200 m, p > 0.20 for 4200 m). In addition, Tibetans had 0.53 g/dL higher carboxyhemoglobin compared to Han Chinese at 2200 m (p = 0.005) independent of sex. Considering Tibetans had lower [Hb] than Han Chinese, higher CO content might suggest increased red blood cell destruction in Tibetans. In summary, among Tibetans, who exhibit significantly lower [Hb] and elevated COHb, females exhibit increased exercise capacity and ventilation compared to Han Chinese females at 2200m, and similar trends were exhibited in males acutely exposed to simulated 4200 m. Male Tibetans exhibited greater DL than Han Chinese counterparts. Trends were further noted for greater QT and DM in Tibetans, which is consistent with our previous studies of Tibetans residents at 4200 m. Therefore, it is evident that unique traits of high‐altitude adaptation of Tibetans are retained at intermediate altitude. Such differences between hypoxic‐exercise responses of Tibetans and Han Chinese are likely innate and may be attributed to genetics. Table 1

An acute increase in hemoglobin concentration ([Hb]) up to 1.6 g/dL has been previously reported under the condition of exercise‐induced hypoxemia in sea level individuals with COPD (Schagatay et.al 2015). Changes in [Hb] have been attributed to splenic contraction. To determine whether, and to what extent, [Hb] changes acutely in response to exercise in long‐term residents at high altitude, we compared hemoglobin concentration at rest and during exercise in male Andean (n = 14; 4330 m) and Tibetan (n = 21; 4200 m) native highlanders, whose ancestors have resided for hundreds of generations at altitude, as well as Han Chinese (n = 9; 4200 m) high‐altitude residents. In the latter two populations, we further examined male (Tibetan n = 10; Han n = 8) and female (Tibetan n = 9; Han n = 10) individuals both at a resident altitude of 2200 m and simulated altitude of 4200 m in a hypobaric chamber. We measured [Hb] at rest ([Hb] _r ), and peak exercise ([Hb] _p ), as well as blood oxygen saturation (SaO2), cardiac output (QT), VO2 and body mass index (BMI) and compared [Hb] _p ‐ [Hb] _r , denoted as Δ[Hb], for male Andeans at 4300 m, male Tibetans and Han Chinese resident at 4200 m, male and female Tibetans and Han Chinese resident at 2200 m and under simulated 4200 m. [Hb] significantly increased with exercise in all groups (P < 0.001 each) except for Han Chinese and Tibetan females at 4200 m. For male Andeans at 4300 m, Δ[Hb] was 1.11 g/dL. For Han Chinese and Tibetans at 2200 m, Δ[Hb] was 1.09 g/dL and 0.94 g/dL, respectively (males), and 1.17 g/dL and 1.01 g/dL respectively (females). For Han Chinese and Tibetans at 4200 m, Δ[Hb] was also significant (p < 0.001) at 1.20 g/dL and 0.87 g/dL respectively in males, but in females the increases were not. No significant difference of Δ[Hb] is observed across different ethnic groups regardless of sex at high altitude. The correlation between Δ[Hb] and SaO2 at maximum exercise level is found to be positive in the Andeans (p = 0.007) and not detected in Tibetans or Han Chinese. In addition, there is no significant correlation found between Δ[Hb] and BMI, [Hb] _r , QT _max or VO2 _max . In conclusion, we observed an exercise‐induced increased [Hb] among Andeans, Tibetans and Han Chinese at high altitude and Tibetans and Han Chinese only at intermediate altitude. Thus, measurement of [Hb] in‐situ during hypoxia/exercise experiments are important to incorporate in studies of O2 transport. Furthermore, larger Δ[Hb] can be potentially beneficial to maintaining higher oxygen saturation at high altitude during acute exercise. [ Hb ]( g / dL ) of Tibetans, Han Chinese and Andeans: Ancestry Tibetans Han Chinese Andeans Exercise Level Rest Peak Rest Peak Rest Peak Male 15.4 ± 1.3 16.2 ± 1.2 16.7 ± 1.3 17.4 ± 1.1 2200 m Female 12.9 ± 1.8 13.5 ± 1.8 13.4 ± 1.2 14.1 ± 1.4 Male 15.1 ± 1.0 16.1 ± 1.4 16.2 ± 1.0 17.1 ± 0.9 17.3 ± 1.6 18.4 ± 1.7 4200 m Female 12.7 ± 1.5 13.1 ± 1.4 13.2 ± 1.3 13.8 ± 1.2